EP4727978A2 - Compositions comprising anti-mutant kras antibodies and methods of use thereof - Google Patents

Abstract

Disclosed herein are anti-mutant KRAS antibodies and methods of using the disclosed anti-mutant KRAS antibodies to treat cancer.

Description

COMPOSITIONS COMPRISING ANTI-MUTANT KRAS ANTIBODIES AND METHODS OF USE THEREOF

I. CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/508,423 filed 15 June 2023, which is incorporated by reference herein in its entirety.

II. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Federal Grant No. CA232758 awarded by the National Cancer Institute and under Federal Grant No. CA278907 awarded by the National Institute of Health. The Federal Government has certain rights to this invention.

III. REFERENCE TO THE SEQUENCE LISTING

[0003] The Sequence Listing submitted 15 June 2024 as an XML file named '23-2091-WO Sequence Li sting', created on 15 June 2024 and having a size of 170 kB is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).

IV. BACKGROUND

[0004] Despite their long half-life, therapeutic antibodies are considered ineffective against intracellular antigens due to their large size, which renders them unable to penetrate the cytoplasm. Therefore, the development of antibody-based immunotherapies has been thus far limited to transmembrane or extracellular targets. However, most oncodrivers underpinning tumorpromoting pathways are intracellular proteins inaccessible to conventional therapeutic antibodies. Considerable efforts have been made to develop small molecules that target these intracellular pathways by inhibiting enzymatic activity or serving as allosteric modulators. Small molecule inhibitors that target oncodrivers offer great therapeutic benefits and have made a big impact in oncology. However, the half-life of many small molecules is approximately 6 hours, which can limit on target interactions. In contrast, the serum half-life of optimized antibodies is > 20, which offers more sustained neutralization and can thus be less frequently dosed.

[0005] Mutant KRAS is an example of an intracellular oncodriver. Oncogenic mutations in KRAS lead to it being permanently bound by GTP (as opposed to GDP) rendering KRAS constitutively active. The mutated KRAS oncogene is found in approximately 90% of pancreatic adenocarcinomas, 40% of colorectal cancer, 30% of lung cancers, and generally in about 20-30% of all human cancers, with the G12D mutation being the most frequent at approximately 43%, representing nearly 50,000 US patients annually. These cancers are particularly difficult to treat - with a tendency to poor outcomes, due to an association between KRAS mutations and lack of response to EGFR tyrosine kinase inhibitors and chemotherapy. [0006] Thus, there remains an unmet medical need for targeting mutant KRAS to enhance the efficacy of cancer therapies and cancer treatments.

V. BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG. 1A - FIG. 1G shows that KRAS^G12D mutation-specific dlgAl, but not IgG4, neutralized KRAS^G12D inside tumor cells and expelled the oncodriver outside tumor cells.

[0008] FIG. 1A shows immunoblots showing that recombinant anti -KRAS ^G12D-Ig Al and anti- KRAS^G12D-IgG4 antibodies specifically recognized the specific mutation in KRAS, and did not bind with G12C or G13D mutated KRAS or WT KRAS (n = 3).

[0009] FIG. IB shows confocal immunofluorescence microscopy images showing that Alexa Fluor 647-conjugated anti-KRAS^G12D-IgAl, but not with anti-KRAS^G12D-IgG4, penetrated KRAS^G12D-mutant A427 and SK-LU-1 NSCLC cells, while KRAS^G12D-specific, but not irrelevant dlgA, co-immunoprecipitated with KRAS^G12D. Scale bar, 25 pm.

[0010] FIG. 1C shows confocal immunofluorescence microscopy showing that treatment with Alexa Fluor 488-conjugated anti-KRAS^G12D-IgAl (middle pane /), but not with anti-KRAS^G12D- IgG4 (right panel), disarrays KRAS^G12D, but not KRAS^W (left panel) tracked by the fusion partner PAmCherry (Red) from KRAS^G12D-PAmCherry-OVCAR3 or KRAS^WT-PAmCherry-OVCAR3 cells, respectively (n = 3). Scale bar, 50 pm

[0011] FIG. ID shows conditioned media from anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA or vehicle (PBS)-treated KRAS^G12D-PAmCherry-OVCAR3 cells were co- immunoprecipitated using anti-human secretory component of plgR and elutes were ran by SDS- PAGE, stained with Ponceau Red, and immunoblotted for KRAS^G12D, IgA, and plgR (n = 3).

[0012] FIG. IE shows immunoblots showing KRAS^G12D levels in anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA-treated KRAS^G12D-OVCAR3 cell lysates.

[0013] FIG. IF shows conditioned media from anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA or vehicle (PBS)-treated KRAS^G12D-PAmCherry-OVCAR3 and KRAS^WT- PAmCherry-OVCAR3 cells were subjected to liquid chromatography with tandem mass spectrometry (LC-MS/MS). Heatmaps showing intensities of mCherry (left panel) and plgR (right panel) peptides detected (n = 3).

[0014] FIG. 1G shows transcytosis experiment by growing KRAS^G12D-OVCAR3 cells in transwell inserts, and adding biotinylated anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA to the upper chamber left . FIG. 1G shows dot blots showing presence of KRAS^G12D (top panel) or beads (bottom panel) in the streptavidin immunoprecipitates of the basal and upper chamber contents (right). [0015] FIG. 2A - FIG. 2B shows that KRAS^G12D-specific dlgAl, but not the same antibody on an IgG4 backbone, captured mutant KRAS during trafficking.

[0016] FIG. 2A shows high resolution confocal microscopy showing that aggregates of KRAS^G12D-specific dlgA, but not KRAS^G12D-specific IgG, co-localized with KRAS^G12D- PamCherry after 1 hr of treatment inside KRAS^G12D-OVCAR3 tumor cells (n = 3). No-wash images confirmed equivalent positive green fluorescence of added KRAS^G12D-specific IgA and IgG antibodies outside of the cells (45 min after treatment), Scale bar, 50 pm or 10 pm, as indicated.

[0017] FIG. 2B shows co-immunoprecipitates of non-denatured lysates (6 mg) of anti-KRAS^G12D- IgAl, anti-KRAS^G12D-IgG4, or vehicle (PBS)-treated KRAS^G12D-OVCAR3 cells using anti- Rab5A, Rab7A, Rab8A, or Rabi 1 A antibodies were immunoblotted for KRAS^G12D, IgA and IgG as appropriate (top panel). 60 pg lysates (1% of co-IP lysate) of anti-KRAS^G12D-IgAl, anti- KRAS^G12D-IgG4, or vehicle (PBS)-treated KRAS^G12D-OVCAR3 cells were immunoblotted for Rab5A, Rab7A, Rab8A, and Rabi 1 A as input control (bottom panel), (n = 3).

[0018] FIG. 3A - FIG. 3F shows mutation-specific dlgA treatment reduces proliferation, without causing apoptosis, of endogenously KRAS^G12D mutated lung cancer and KRAS^G12D-transduced, but not KRAS^{w l}-transduced ovarian cancer cells.

[0019] FIG. 3A shows MTT assay-based absorbance at 570 nm of KRAS^G12D -transduced OVCAR3 cells treated with irrelevant IgA or anti-KRAS^G12D IgAl, relative to mean absorbance of vehicle (PBS) treated cells, at different temporal points (n = 8).

[0020] FIG. 3B shows MTT assay -based absorbance at 570 nm of KRAS^wl -transduced OVCAR3 cells treated with irrelevant IgA or anti-KRAS^G12D IgAl, relative to mean absorbance of vehicle (PBS) treated cells, at different temporal points, (n = 8).

[0021] FIG. 3C shows MTT assay -based absorbance at 570 nm of untransduced OVCAR3 cells treated with irrelevant IgA or anti-KRAS^G12D IgAl, relative to mean absorbance of vehicle (PBS) treated cells, at different temporal points, (n = 16).

[0022] FIG. 3D shows MTT assay-based absorbance at 570 nm of SK-LU-1 cells treated with irrelevant IgA or anti-KRAS^G12D IgAl, relative to mean absorbance of vehicle (PBS) treated cells, at different temporal points, (n = 16).

[0023] FIG. 3E shows MTT assay-based absorbance at 570 nm of HEK293T cells treated with irrelevant IgA or anti-KRAS^G12D IgAl, relative to mean absorbance of vehicle (PBS) treated cells, at different temporal points, (n = 16).

[0024] FIG. 3F shows bar graphs showing total apoptotic cells, determined by flow cytometry analysis of KRAS^G12D-transduced OVCAR3 cells, treated with vehicle, or irrelevant IgA, or anti- KRAS^G12D IgAl, or anti-KRAS^G12D IgA4 antibodies, and gating total Annexin v^p0Sltlve cells (n = 3). Data are mean ± SEM. ***p < 0.001, NS, not significant; unpaired two-tailed t-test. TABLE 5A - TABLE 5Z provides details of statistics.

[0025] FIG. 4A - FIG. 4E shows that KRAS^G12D-specific dlgAl, but ot the same antibody on an IgG4 backbone, abrogated KRAS^G12D tumor growth in vivo.

[0026] FIG. 4A shows a schematic of design of experiment shown in FIG. 4B and FIG. 4C. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) was intratum orally (IT) injected.

[0027] FIG. 4B shows tumor growth curves (left), tumor weight (right) in KRAS^G12D-OVCAR3 tumor-bearing Ragl -deficient mice receiving control IgA, or anti-KRAS^G12D-IgAl, or anti- KRAS^G12D-IgG4 antibodies, or vehicle, IT. Growth curves and tumor weights were pooled from 2 independent experiments (n = 10 mice per group).

[0028] FIG. 4C shows tumor growth curves in mice (left), tumor weight (right) in KR.AS^WI - OVCAR3 tumor-bearing Ragl -deficient mice receiving control IgA, or anti-KRAS^G12D-IgAl, or anti-KRAS^G12D-IgG4 antibodies, or vehicle, IT. Growth curves and tumor weights were pooled from 2 independent experiments (n = 10 mice per group).

[0029] FIG. 4D shows a schematic of design of experiment. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) or MRTX1133 at 200 pg per 20 g body weight was intraperitoneally (IP) inj ected every 4 d or daily. Tumor growth curves (left), tumor weight (right) in KRAS^G12D-OVCAR3 tumor-bearing NSG mice receiving anti-KRAS^G12D-IgAl, or MRTX1 133, or vehicle, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 13 mice per group). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights.

[0030] FIG. 4E shows a representative immunohistochemical staining for human IgA of KRAS^G12D-OVCAR3 mice tumors treated intraperitoneally with non-antigen specific or KRAS^G12D-specific dlgA. Scale bar, 400 or 60 pm, as indicated. TABLE 5A - TABLE 5Z provides details of statistics.

[0031] FIG. 5A - FIG. 5G shows that IgA coated PIGR⁺ NSCLC tissues, while KRAS^G12D- specific dlgAl was more effective than small molecule KRAS^G12D inhibitors at abrogating the progression of NSCLCs spontaneously driven by KRAS^G12D.

[0032] FIG. 5A shows representative (n = 30) combined staining of plgR, IgA, IgG, CD3, Pan cytokeratin (panCK) and DAPI. Scale bar, 200 pm (upper panel), 100 pm (magnified lower panels). [0033] FIG. 5B shows that the accumulation of CD3⁺ T cells in the panCK⁺ tumor islets was associated with increase in the coating of the tumor cells by IgA and IgG, expression of plgR and co-localization of IgA with plgR. Data are mean ± SEM. **P < 0.01; ***P < 0.001, unpaired two- tailed t-test.

[0034] FIG. 5C shows a schematic of design of experiment shown in FIG. 5D and FIG. 5E. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) every 4 d or MRTX1 133 at 200 pg per 20 g body weight daily or every 4 d was injected IP.

[0035] FIG. 5D shows tumor growth curves in A427 tumor-bearing NSG mice receiving anti- KRAS^G12D-IgAl, or anti-KRAS^G12D-IgG4 every 4 d, or MRTX1133 every 4 d (left) or daily (middle), or vehicle every 4 d, IP. Tumor weight (right) in A427 tumor-bearing NSG mice receiving anti-KRAS^G12D-IgAl, or anti -KRAS ^G12D-IgG4 every 4 d, or MRTX1133 every 4 d or daily, or vehicle every 4 d, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 14 mice per group).

[0036] FIG. 5E shows a western blot showing phosphorylated and total ERK1/2 in lysates of KRAS^G12D-mutant A427 cells, treated with anti-KRAS^G12D-IgAl or MRTX1133.

[0037] FIG. 5F shows the identical treatment as shown in FIG. 5D of advanced KRAS^G12D- mutated SK-LU-1 lung cancers. Growth curves and tumor weights were pooled from 3 independent experiments (n = 14 mice per group).

[0038] FIG. 5G shows a schematic design of treatments in KPMSH2^KIN lung tumor-bearing immunocompetent mice (left). Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) was intraperitoneally injected. CD8 T cells were also depleted with intraperitoneal anti- CD8 antibodies., Tumor growth curves in mice receiving intraperitoneal vehicle or anti- KRAS^G12D-dIgAl, or anti-IDHl^R132H-dIgAl, with or without CD8 T cell depletion (right). Growth curves were pooled from 2 independent experiments (n = 8-10 mice per group). Data are mean ± SEM. *P < 0.05, **p < 0.01, *** < 0.001; paired two-tailed t-test (FIG. 5D and FIG. 5F) and non-parametric Wilcoxon test (FIG. 5G) for growth curves or unpaired two-tailed t-test for tumor weights. TABLE 5A - TABLE 5Z provides details of statistics.

[0039] FIG. 6A - FIG. 6G. IDHl^R132H-specific dlgAl abrogated IDHl-mutated colon cancer growth in vivo in a PIGR expression-dependent manner.

[0040] FIG. 6A shows immunoblots showing that recombinant anti-IDHl^R132H-IgAl antibodies specifically recognize the mutation in the lysates of ¹³²¹¹ HCT116 cells but not of IDH1^{+ +} HCT116 cells, with or without PIGR -transduction, and confirm ov erexpression of plgR in the /GA-transduced cells (n = 3). [0041] FIG. 6B shows schematic of design of experiment shown in FIG. 6C - FIG. 6F. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) was injected IP.

[0042] FIG. 6C shows tumor growth curves (left), tumor weight (middle), tumor volume of one representative experiment (right) in untransduced (pIgR^low) mutant-IDHl (//J/// ^{R I 32H}) tumorbearing NSG mice receiving control IgA, or anti-IDHl^G12D-IgAl, or vehicle, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 14 mice per group).

[0043] FIG. 6D shows tumor growth curves left), tumor weight middle), tumor volume of one representative experiment (right) in untransduced (pIgR^low) WT-IDH1 (IDH1^{+ +}) tumor-bearing NSG mice receiving control IgA, or anti-IDHl^G12D-IgAl, or vehicle, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 15 mice per group).

[0044] FIG. 6E shows tumor growth curves (left), tumor weight (middle), tumor volume of one representative experiment (right) in E/G7 -transduced mutant-IDHl (ZDJ77^+/R132H) tumor-bearing NSG mice receiving control IgA, or anti-IDHl^G12D-IgAl, or vehicle, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 16 mice per group).

[0045] FIG. 6F shows tumor growth curves (left), tumor weight (middle), tumor volume of one representative experiment (right) in 7G7?-transduced WT-IDH1 (IDH1^{+ +}) tumor-bearing NSG mice receiving control IgA, or anti-IDHl^G12D-IgAl, or vehicle, IP. Growth curves and tumor weights were pooled from 3 independent experiments (n = 16 mice per group).

[0046] FIG. 6G shows a schematic of design of experiment. Monomeric or dimeric anti- IDHi^Gi^2D-igAl or anti-IDHl^G12D-IgG4 antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) was injected IP in mutant-IDHl (7D777^+/R132H) tumor-bearing NSG mice. Growth curves pooled from 2 independent experiments (n = 8-9 mice per group). Data are mean ± SEM. *P < 0.05, ***P < 0.001, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights. TABLE 5A - TABLE 5Z provides details of statistics.

[0047] FIG. 7A - FIG. 7B show PIGR mRNA expression across cancer types.

[0048] FIG. 7A shows TCGA data showing PIGR mRNA expression, expressed as RNA Seq V2 RSEM (log2(value+l)) in several epithelial and non-epitheli al malignancies.

[0049] FIG. 7B shows native human IgA was subjected to mass spectrometry. Two unique peptides, one is from amino acid 47 to 58 (SSEDPNEDIVER) (SEQ ID NO: 112) and the other from amino acid 61-69 (IIVPLNNR) (SEQ ID NO: 113), of human J-chain were identified (left). FIG. 7C shows native gel electrophoresis of two different lot of native human IgA procured from Abeam (ab91025), which showed the presence of both dimeric and monomeric IgA in the gel at their corresponding molecular weights (right). [0050] FIG. 8A - FIG. 8F. Production and purification of KRAS^G12D and IDH1R132H mutation specific recombinant dlgAl and IgG4 antibodies.

[0051] FIG. 8A shows immunoblots using denatured lysates of transduced HEK293T cells confirming expression of alpha or gamma heavy chain, kappa light chain, specific for KRAS^G12D or IDH1^R132H dlgAl or IgG4, and J-chain for dimeric IgAl (n = 3). FIG. 8B has graphs showing peaks of purified anti-human KRAS^G12D and IDH1^R132H dlgA and IgG4 antibodies 280 nm. FIG. 8C shows a native gel electrophoresis of different IgA antibodies that shows the presence of dimeric and monomeric IgA in the gel at their corresponding molecular weights. FIG. 8D shows immunoblots showing that recombinant anti -KRAS mut-Ig Al and anti- KRASmut-IgG4 antibodies specifically recognize mutant KRAS^G12D, in the lysates of KRAS^G12D- PAmCherry- OVCAR3, but not KRASWT-PAmCherry-OVCAR3 cells, as well as lung cancer cell lines A427 and SK-LU-1 as well as. Anti-mCherry antibody recognized KRASWT-PAmCherry and KRAS^G12D-PAmCherry fusion proteins in transduced OVCAR3 lysates (n = 3). FIG. 8E shows immunoblots showing KRAS^G12D levels in anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA-treated KRAS^G12D-A427 lung cancer cell lysates. FIG. 8F shows a transcytosis experiment by growing KRAS^G12D-OVCAR3 cells in transwell inserts, and adding biotinylated anti-KRAS^G12D-IgAl/IgG4 or non-antigen specific irrelevant IgA to the upper chamber. Dot blots showing presence of KRAS^G12D (left panel), human IgA (middle panel), or human IgG (right panel) in the streptavidin immunoprecipitates of the basal and upper chamber contents.

[0052] FIG. 9A - FIG. 9C show the intratumoral infusion of KRAS^G12D-specific dlgAl, but not the same antibody on an IgG4 backbone abrogates KRAS^G12D-OVCAR3, but not KRASWT- OVCAR3 tumor growth, superior to control IgA and MRTX1133, in Rag 1 -deficient mice. FIG. 9A shows a schematic of design of experiment shown in FIG. 9B, and FIG. 9C. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) was intratum orally (IT) injected every 4 d, or MRTX1133 at 200 pg per 20 g body weight was intraperitoneally (IP) injected every 4 d or daily. FIG. 9B shows tumor growth curves (left), tumor weight (middle), tumor volume (right) in KRAS^G12D-OVCAR3 tumor- bearing Rag-/- mice. Growth curves and tumor weights were pooled from 2 independent experiments (n = 10 mice per group). FIG. 9C shows tumor growth curves (left), tumor weight (middle), tumor volume (right) in KRASWT-OVCAR3 tumor-bearing Rag-/- mice. Growth curves and tumor weights were pooled from 2 independent experiments (n = 10 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***p < 0.001, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights. TABLE 5A - TABLE 5Z provides details of statistics. [0053] FIG. 10A - FIG. 10B show intraperitoneal infusion of KRAS^G12D-specific dlgAl, but not the same antibody on an IgG4 backbone abrogates KRAS^G12D-OVCAR3, but not KRASWT- OVCAR3 tumor growth, superior to control IgA and MRTX1133, in NSG mice.

[0054] FIG. 10A is a schematic of design of experiment shown in FIG. 10B. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) every 4 d or MRTX1133 at 200 pg per 20 g body weight every 4 d or daily was intraperitoneally (IP) injected. FIG. 10B shows tumor growth curves (top), tumor weight (bottom left), representative tumor volume of one experiment (bottom right) in KRAS^G12D-OVCAR3 tumor- bearing NSG mice. Growth curves and tumor weights were pooled from 3 independent experiments (n = 13 mice per group). Data are mean ± SEM. *P < 0.05, ***p < 0.001, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights. TABLE 5A - TABLE 5Z provides details of statistics.

[0055] FIG. 11A - FIG. HE show intraperitoneal infusion of KRAS^G12D-specific dlgAl, but not the same antibody on an IgG4 backbone abrogated A427 or SK-LU-1 tumors, superior to control IgA and MRTX1133, in NSG mice. FIG. HA shows bar graphs showing comparisons of percentages of CD3+ cells, PIGR+ cells, IgA-coated cells, and IgG-coated cells within the PCK+ tumor islets among adenocarcinoma and squamous cell carcinoma histology types, (n = 12 each, with two duplicated cores). NS, not significant; Unpaired two-tailed t-test. FIG. 11B shows a schematic of design of experiment shown in FIG. 11C and FIG. HD. Antibody at 100 pg per 20 g body weight or equal volume of vehicle (PBS) every 4 d or MRTX1133 at 200 pg per 20 g body weight daily or every 4 d was injected IP. FIG. 11C shows tumor growth curves (top), tumor weight (bottom, left), tumor volume (bottom, right) in A427 tumor-bearing NSG mice. Growth curves and tumor weights were pooled from 3 independent experiments (n = 14 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.01, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights. FIG. HD shows tumor growth curves top), tumor weight (bottom, left), tumor volume (bottom, right) in SK-LU-1 tumor-bearing NSG mice. Growth curves and tumor weights were pooled from 3 independent experiments (n = 14 mice per group). FIG. HE shows schematic design of treatments in KRAS^G12D Brpkpl lO tumor-bearing immunocompetent mice (left). Antibody at 100 pg per 20 g body weight was intraperitoneally injected. Middle, tumor growth curves and right, tumor weights in mice receiving intraperitoneal anti-KRAS^G12D-dIgAl, or anti-KRAS^G12D-IgG4, or non-specific dlgA. Growth curves and tumor weights were pooled from 2 independent experiments (n = 10 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.01, NS, not significant; paired two-tailed t-test for growth curves or unpaired two-tailed t-test for tumor weights. TABLE 5A - TABLE 5Z provides details of statistics.

[0056] FIG. 12A shows a scheme of modifications in recombinant IgG4 to make them trigger PIGR-mediated transcytosis. FIG. 12B shows a schematic for treatment using lung tumor model, treatments were repeated 4 times, and tumor growth was monitored for 2 weeks (until day 21-23 after initial tumor challenge) FIG. 12C shows tumor growth curves confirming that the modified IgG was capable of delaying tumor growth as effectively as dlgA in vivo, using a transplantable p53/KRAS^G12D/MSH2-driven lung cancer model in immunocompetent B6 mice.

[0057] FIG. 13A shows confocal microscopy showing penetration of green fluorescently labeled modified IgG4 (IgG#3; bottom) inside PIGR+ OVACR3 cells (50 min; wash after 20 min). Top, bright field. FIG. 13B shows biotinylated PIGR-binding a-KRAS^G12D (IgG#3) added to a transwell system, with confluent KRAS^G12D A427 or KRAS^G12D-transduced OVCA3 cells (left) while dot blots showed KRAS^G12D in the streptavidin immunoprecipitates of supernatants (right). [0058] FIG. 14A shows four different formulations of KRAS^G12D-targeting IgG4, with different CDS sequences. IgG#3 is a humanized Ab. FIG. 14B shows the effectiveness of the antibodies of FIG. 14A at controlling the growth of established endometrial tumors in vivo (100 pg/injection, 5 injections; 5 mice/group). FIG. 14C shows the formulation of IgG#4 without GS spacer compared to IgG#0. FIG. 14D shows that addition of the PIGR-binding peptide at the C-terminus of the Fc domain, without a GS spacer (IgG#4), was less effective.

[0059] FIG. 15A shows the schematic of the experiments while FIG. 15B shows that SEL39-003 (IgG4) effectively controlled the growth of spontaneously mutated NSCLC in vivo. FIG. 15C shows that IgG#0 was internalized into A427 NSCLC cells.

VI. BRIEF SUMMARY

[0060] Disclosed herein is an anti-mutant KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS.

[0061] Disclosed herein is an antibody recognizing the GTP -bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS. [0062] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising any disclosed VL including, for example, those listed in Table 3.

[0063] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising any disclosed VH including, for example, those listed in Table 4. [0064] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VL comprising any disclosed CDR including, for example, those listed in Table 1.

[0065] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VH comprising any disclosed CDR including, for example, those listed in Table 1.

[0066] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a combination of any disclosed VL and any disclosed VH, such as, for example, those disclosed in Table 3 and Table 2, respectively.

[0067] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VL and a VH, each comprising a combination of any disclosed CDRs such as, for example, those disclosed in Table 1.

[0068] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 14, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 10.

[0069] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:22, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 18.

[0070] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 100, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 96.

[0071] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 108, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 104.

[0072] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:33, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:26.

[0073] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:44, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:37.

[0074] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:57, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:50.

[0075] Disclosed herein is anti-mutant KRAS antibody comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP -bound active form of KRAS.

[0076] Disclosed herein is antibody recognizing the GTP -bound active conformation of mutant KRAS comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP- bound active form of KRAS.

[0077] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 67, and (ii) a VH having the sequence set forth in SEQ ID NO: 63. [0078] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 75, and (ii) a VH having the sequence set forth in SEQ ID NO:71. [0079] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:83, and (ii) a VH having the sequence set forth in SEQ ID NO:79. [0080] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:67, SEQ ID NO:75, or SEQ ID NO:83, and (ii) a VH having the sequence set forth in any one of SEQ ID NO: 115 - SEQ ID NO: 119.

[0081] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:67, SEQ ID NO:75, or SEQ ID NO:83, and (ii) a VH having the sequence set forth in any one of SEQ ID NO: 121, SEQ ID NO: 122, or SEQ ID NO: 123.

[0082] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed antimutant KRAS antibody.

[0083] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 05, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:OL

[0084] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 05, and (ii) a VH, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 114. [0085] Disclosed herein is a method for treating a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-mutant KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies.

[0086] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more disclosed anti-mutant KRAS antibodies.

[0087] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0088] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the anti-mutant KRAS antibody having an IgG backbone comprise any VL listed in Table 3 and any VH listed in Table 2.

[0089] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the anti-mutant KRAS antibody having a dimeric IgA backbone comprise any VL listed in Table 3 and any VH listed in Table 2.

VII. DETAILED DESCRIPTION

[0090] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and/or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0091] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

A. Definitions [0092] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0093] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0094] As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0095] The phrase 'consisting essentially of limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase 'consisting of excludes any component, step, or element that is not recited in the claim. The phrase 'comprising' is synonymous with 'including', 'containing', or 'characterized by', and is inclusive or open-ended. 'Comprising' does not exclude additional, unrecited components or steps. [0096] As used herein, when referring to any numerical value, the term 'about' means a value falling within a range that is ± 10% of the stated value.

[0097] Ranges can be expressed herein as from 'about' one particular value, and/or to 'about' another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent 'about,' it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as 'about' that particular value in addition to the value itself. For example, if the value TO' is disclosed, then 'about 10' is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0098] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0099] As used herein, the terms 'optional' or 'optionally' means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0100] As used herein, the term 'subject' refers to the target of administration, e.g., a human being. The term 'subject' also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject of the herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have cancer, be suspected of having cancer, or be at risk of developing cancer.

[0101] As used herein, the term 'diagnosed' means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. For example, 'diagnosed with a disease or disorder' means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as a mutant KRAS-driven cancer) that can be treated by one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. For example, "suspected of having a disease or disorder" can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as a mutant KRAS- driven cancer) that can likely be treated by one or more disclosed anti -mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.), scans (e.g., CT scans, PET scans, etc.), and assays (e.g., enzymatic assay), or a combination thereof.

[0102] A "patient" refers to a subject afflicted with a disease or disorder (e.g., a mutant KRAS- driven cancer). In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder such as a mutant KRAS-driven cancer. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder and is seeking treatment or receiving treatment for a disease or disorder (such as mutant KRAS-driven cancer).

[0103] As used herein, the phrase "identified to be in need of treatment for a disease or disorder," or the like, refers to selection of a subj ect based upon need for treatment of the disease or di sorder. For example, a subject can be identified as having a need for treatment of a disease or disorder (e.g., a mutant KRAS-driven cancer) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the cancer. In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0104] As used herein, "activated" and "activation" can refer to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production and detectable effector functions. The term "activated T cells" can refer to T cells that are proliferating. Signals generated through the TCR alone may be insufficient for full activation of the T cell and one or more secondary or costimulatory signals may also be required. Thus, T cell activation comprises a primary stimulation signal through the TCR/CD3 complex and one or more secondary costimulatory signals. Costimulation can be evidenced by proliferation and/or cytokine production by T cells that have received a primary activation signal, such as stimulation through the TCR/CD3 complex.

[0105] As used herein, "inhibit," "inhibiting", and "inhibition" mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or other biological parameter as compared to the native or control level (e.g., a subject not having received one or more disclosed anti -mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof). Thus, in an aspect, the inhibition or reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., a subject not having received one or more of the disclosed anti -mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof). In an aspect, the inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels. In an aspect, a native or control level can be a pre-disease or pre-disorder level (such as a pre-cancer state).

[0106] The words "treat" or "treating" or "treatment" include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder (e.g., a mutant KRAS-driven cancer); preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder (e.g., a mutant KRAS-driven cancer); and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder (e.g., a mutant KRAS- driven cancer). In an aspect, the terms cover any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, i.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease. For example, in an aspect, treating a disease or disorder can reduce the severity of an established a disease or disorder in a subject by 1%-100% as compared to a control (such as, for example, an individual not having cancer). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of a disease or disorder (e.g., a mutant KRAS-driven cancer). For example, treating a disease or disorder can reduce one or more symptoms of a disease or disorder in a subject by 1 %-l 00% as compared to a control (such as, for example, an individual not having cancer). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction of one or more symptoms of an established a disease or disorder (e.g., a mutant KRAS- driven cancer). It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a disease or disorder. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of a disease or disorder (such as a mutant KRAS-driven cancer). [0107] As used herein, the term "prevent" or "preventing" or "prevention" refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. In an aspect, preventing a disease or disorder having chromatin deregulation and/or chromatin dysregulation is intended. The words "prevent", "preventing", and "prevention" also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given a disease or disorder (such as a mutant KRAS-driven cancer) or related complication from progressing to that complication. In an aspect, preventing metastasis is intended.

[0108] As used herein, the terms "administering" and "administration" refer to any method of providing one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, the following: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intratumoral administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intraarterial administration or administration through the hepatic portal vein (HPV). Administration of one or more disclosed anti -mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof can comprise administration directly into the CNS orthePNS. Administration can be continuous or intermittent. Administration can comprise a combination of one or more routes.

[0109] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to treat or prevent a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof.

[0110] By "determining the amount" is meant both an absolute quantification of a particular analyte (e.g., biomarker for mutant KRAS-driven cancer, for example) or a determination of the relative abundance of a particular analyte (e.g., a mutant KRAS-driven cancer biomarker). The phrase includes both direct or indirect measurements of abundance or both.

[0111] As used herein, "modifying the method" can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. In an aspect, a method can be altered by changing the amount of the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to a subject, by changing the duration of time that one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof is administered to a subject, or by substituting for one or more of the disclosed components and/or reagents with a similar or equivalent component and/or reagent. The same applies to all disclosed anti-mutant KRAS antibodies, disclosed isolated nucleic acid molecules, disclosed vectors disclosed cells, disclosed pharmaceutical formulations, and any combination thereof.

[0112] As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0113] As used herein, the term "excipient" refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference, Remington's Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.

[0114] A "transposon" is a mobile genetic element that efficiently moves between vectors and chromosomes using the "cut and paste" or "copy and paste" mechanism. During transposase transposition (for example, PB transposase in the PiggyBac transposon system) recognizes transposon-specific sequences of inverted terminal repeats (ITRs) located at both ends of the transposon (there are 5'- and 3'-ITRs in any transposon system), it moves the contents from source sites and embeds them in chromosomal sites, such as TTAA chromosomal sites. In an aspect, the powerful activity of the PiggyBac transposon system makes it easy to transfer genes of interest located between two ITRs to target genomes. The transposon can be divided into Class I transposon (retrotransposon) and Class II transposon (DNA transposon). In Class I transposon, after RNA is transcribed from nucleic acid in a cell or from transposon DNA on the animal genome, the DNA reverse-transcribed from the RNA is transferred to another location on the animal genome. It works by inserting it. Class II transposon cuts nucleic acid in cells or transposon DNA on the animal genome, and then inserts the cut transposon DNA into another location on the animal genome. The Class II transposon may include a first polynucleotide at a 5' end, a second polynucleotide at a 3' end, and a third polynucleotide. The first polynucleotide and the second polynucleotide may include an inverted terminal repeat (ITR) sequence. The third polynucleotide may be located between the first polynucleotide and the second polynucleotide. The third polynucleotide may include an exo-polynucleotide. The third polynucleotide may include a polynucleotide encoding a transposase. Unless otherwise specified below, the term "transposon" assumes the case of Class II transposon, but even if the term "transposon" is interpreted as Class I transposon, it is technically If there is no problem, it will not be necessary to limit the interpretation to Class II transposon.

[0115] As used herein, "concurrently" means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0116] In an aspect, the term "contacting" refers to bringing one or more disclosed anti -mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof together with a target area or intended target area in such a manner that the disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anticancer agents, the disclosed chemotherapeutics, or any combination thereof can exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject's organs (e.g., lungs, heart, liver, kidney, brain, etc.) hosting cancerous cells. In an aspect, a target area or intended target area can be any cell or any organ infected by a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, a target area or intended target area can be any organ, tissue, or cells that are affected by a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, a target or intended target can be a blood-borne cancer or a hematologic cancer.

[0117] As used herein, "determining" can refer to measuring or ascertaining the presence and severity of a disease or disorder, such as, for example, a hematologic cancer. Methods and techniques used to determine the presence and/or severity of a disease or disorder are typically known to the medical arts. For example, the art is familiar with the ways to identify and/or diagnose the presence, severity, or both of a disease or disorder (such as, for example, cancer).

[0118] As used herein, "effective amount" and "amount effective" can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and/or prevention of a disease or disorder (e.g., a mutant KRAS-driven cancer) or a suspected disease or disorder (e.g., a mutant KRAS-driven cancer). As used herein, the terms "effective amount" and "amount effective" can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition e.g., a mutant KRAS-driven cancer). For example, a "therapeutically effective amount" refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. In an aspect, "therapeutically effective amount" means an amount of one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anticancer agents, the disclosed chemotherapeutics, or any combination thereof that (i) treats the particular disease, condition, or disorder (e.g., a mutant KRAS-driven cancer), (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder e.g., a mutant KRAS-driven cancer), or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., a mutant KRAS-driven cancer). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereof employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereof employed; the duration of the treatment; drugs used in combination or coincidental with the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereof employed, and other like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition, such as, for example, a mutant KRAS-driven cancer.

[0119] The term "antibody" (Ab) includes, without limitation, a glycoprotein immunoglobulin that binds specifically to an antigen. An antibody can comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain can comprise a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can comprise three constant domains, CHI, CH2 and CH3. Each light chain can comprise a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region can comprise one constant domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL can comprise three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains can contain a binding domain that interacts with an antigen. The constant regions of the Abs can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Generally, human antibodies can be approximately 150 kD tetrameric agents composed of two identical heavy (H) chain polypeptides (about 50 kD each) and two identical light (L) chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a "Y-shaped" structure. The heavy and light chains can be linked or connected to one another by a single disulfide bond and two other disulfide bonds can connect the heavy chain hinge regions to one another, so that the dimers can be connected to one another and the tetramer can be formed. Naturally produced antibodies are also glycosylated, e.g., on the CH2 domain. The term "antibody" is used to mean an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing etc., through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies generated from at least two intact antibodies, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD. IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl. IgG2, IgG3. IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0120] The term "variable region" or "variable domain" is used interchangeably. The variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In an aspect, the variable region can be a human variable region. In an aspect, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In an aspect, the variable region is a primate (e.g., non-human primate) variable region. In an aspect, the variable region comprises rodent or murine CDRs and primate framework regions (FRs).

[0121] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody or an antigen-binding molecule thereof. The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody or an antigen-binding molecule thereof.

[0122] As used herein, "conjugate" or "conjugated" can be used to define the operative association of one disclosed component to another disclosed component. In an aspect, conjugated does not intend to refer solely to any type of operative association and is not particularly limited to chemical "conjugation".

[0123] As known to the skilled person, IgG can bind to cell surface receptors on many types of cells to bring about an assortment of effects, for example, (i) the enabling of phagocytosis (e.g., monocytes, macrophages, neutrophils), (ii) antibody-dependent cellular cytotoxicity (monocytes, macrophages and lymphocytes), or (iii) to effect feedback control on antibody synthesis (B and T lymphocytes). In an aspect, the properties of the IgG subclasses can very, and in most cases the Fc fragments can have the same property as the intact IgG; meaning that it does not appear to be modulated by the hinge or the Fab. In an aspect, cellular Fc receptors can be classified into three categories according to structure and affinity. All the sites on IgG that can interact with these separate receptors appear to be located in the Fc region, and, in the case of the FcyRI (which is the highest affinity receptor class), the site involves residues 233-237, at the N-terminal end of the Cy2 domain close to the hinge region but coded in the Cy2 exon.

[0124] "Endogenous" with reference to a gene, protein, and/or nucleic acid refers to the natural presence of that gene, protein, and/or nucleic acid in a cell, such as an immune cell.

[0125] "Exogenous" refers to an introduced agent, such as a nucleic acid, gene, or protein, into a cell, for example from an outside source. A nucleic acid introduced into a cell is exogenous even if it encodes a protein which is naturally found in the cell. Such exogenous introduction of a nucleic acid encoding a protein can be used to increase the expression of the protein over the level that would naturally be found in the cell under similar conditions, e.g., without introduction of the exogenous nucleic acid.

[0126] A "T cell receptor" or "TCR" refers to antigen-recognition molecules present on the surface of T cells. During normal T cell development, each of the four TCR genes, a, 0., y, and 6, may rearrange leading to highly diverse TCR proteins. [0127] As used herein, "effector function" can refer to a biological result of interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions comprise, without limitation, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement mediated cytotoxicity (CMC). An effector function may be antigen binding dependent, antigen binding independent, or both. ADCC refers to lysis of antibody -bound target cells by immune effector cells. ADCC is generally understood to involve Fc receptor (FcR)-bearing effector cells recognizing and subsequently killing antibody-coated target cells (e.g., cells that express on their surface antigens to which an antibody is bound). Effector cells that mediate ADCC may comprise immune cells, comprising yet not limited to, one or more of natural killer (NK) cells, macrophages, neutrophils, eosinophils.

[0128] The term "immunotherapy" refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy can include, but are not limited to, NK cells and T cell therapies, NK CAR T-cell and CAR T-cells therapies, and vaccines. T cell therapy can include adoptive T cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACTTM), and allogeneic T cell transplantation. However, one of skill in the art would recognize that the conditioning methods disclosed herein would enhance the effectiveness of any transplanted T cell therapy. The T cells or NK cells of the immunotherapy can come from any source known in the art. For example, T cells and NK cells can be differentiated in vitro from a hematopoietic stem cell population (for example iPSCs) or can be obtained from a subj ect. T cells and NK cells can be obtained from, e.g., peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood collected from a subject using techniques known to the skilled person.

[0129] "Chimeric antigen receptor" or "CAR" refers to a molecule engineered to comprise a binding domain and a means of activating immune cells (for example T cells such as naive T cells, central memory T cells, effector memory T cells, NK cells or combination thereof) upon antigen binding. CARs are also known as artificial T cell receptors, chimeric T cell receptors or chimeric immunoreceptors. In an aspect, a CAR comprises a binding domain, an extracellular domain, a transmembrane domain, one or more co-stimulatory domains, and an intracellular signaling domain. A T cell that has been genetically engineered to express a chimeric antigen receptor may be referred to as a CAR T cell. Similarly, an NK cell that has been genetically engineered to express a chimeric antigen receptor may be referred to as a CAR NK cell.

[0130] Chimeric antigen receptors (CARs) are proteins which graft the specificity of a monoclonal antibody (mAb) to the effector function of a T-cell. CARs comprise an extracellular ligandbinding domain, most commonly a single chain variable fragment (scFv), a spacer domain, a transmembrane domain, and one or more cytoplasmic domains.

[0131] As used herein, the term "humanized antibody" refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster, etc.) that have the desired specificity, affinity, and capability. In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody can be further modified by the substitution of additional residue either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or capability. In general, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.

[0132] That an antibody "selectively binds" or "specifically binds" to an epitope or receptor means that the antibody reacts or associates more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope or receptor than with alternative substances, including unrelated proteins. "Selectively binds" or "specifically binds" means, for instance, that an antibody binds to a protein with aKD of about 0.1 mM or less, more usually about 1 pM or less. "Selectively binds" or "specifically binds" means at times that an antibody binds to a protein with a KD of about 0.1 mM or less, at times about 1 pM or less, at times about 0.1 pM or less, at times about 0.01 pM or less, and at times about 1 nM or less. It is understood that, in an aspect, an antibody or binding moiety that specifically binds to a first target may or may not specifically bind to a second target. As such, "specific binding" does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target. [0133] A "target" or "target antigen" is any molecule bound by a binding motif (e.g., a PIGR- expressing cancer cell). A disclosed target can be cells and/or tissues in a subject.

[0134] In an aspect, PIGR or polymeric immunoglobulin receptor plays a unique role in the mucosal immune system, acting both as an epithelial transporter and as an integral component of secretory immunoglobulins. The human plgR gene (NCBI gene ID: 5284) is located on the q32.1 region of chromosome 1. With a total of 11 exons, the human plgR gene spans about 19 kb.

[0135] "Antigen-specific targeting region" (ASTR) refers to the region of a disclosed anti -mutant KRAS antibody that targets specific antigens. In an aspect, the antigen-specific targeting regions comprise an antibody or a functional equivalent thereof or a fragment thereof or a derivative thereof and each of the targeting regions target a different antigen. The targeting regions may comprise full length heavy chain, Fab fragments, single chain Fv (scFv) fragments, divalent single chain antibodies or diabodies, each of which are specific to the target antigen.

[0136] The term "autologous" refers to any material derived from the same individual to which it is later to be re-introduced. For example, a subject's own cells can be obtained, made to express one or more disclosed CARs, and then administered to the same subject.

[0137] As used herein, "RNA therapeutics" can refer to the use of oligonucleotides to target RNA. RNA therapeutics can offer the promise of uniquely targeting the precise nucleic acids involved in a particular disease with greater specificity, improved potency, and decreased toxicity. This could be particularly powerful for genetic diseases where it is most advantageous to aim for the RNA as opposed to the protein. In an aspect, a therapeutic RNA can comprise one or more expression sequences. As known to the art, expression sequences can comprise an RNAi, shRNA, mRNA, non-coding RNA (ncRNA), an antisense such as an antisense RNA, miRNA, morpholino oligonucleotide, peptide-nucleic acid (PNA) or ssDNA (with natural, and modified nucleotides, including but not limited to, LNA, BNA, 2'-0-Me-RNA, 2'-ME0-RNA, 2'-F-RNA), or analog or conjugate thereof. In an aspect, a disclosed therapeutic RNA can comprise one or more long noncoding RNA (IncRNA), such as, for example, a long intergenic non-coding RNA (lincRNA), pretranscript, pre-miRNA, pre-mRNA, competing endogenous RNA (ceRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), pseudo-gene, rRNA, or tRNA. In an aspect, ncRNA can be piwi -interacting RNA (piRNA), primary miRNA (pri-miRNA), or premature miRNA (pre- miRNA). In an aspect, a disclosed therapeutic RNA or an RNA therapeutic can comprise antisense oligonucleotides (ASOs) that inhibit mRNA translation, oligonucleotides that function via RNA interference (RNAi) pathway, RNA molecules that behave like enzymes (ribozymes), RNA oligonucleotides that bind to proteins and other cellular molecules, and ASOs that bind to mRNA and form a structure that is recognized by RNase H resulting in cleavage of the mRNA target. In an aspect, RNA therapeutics can comprise RNAi and ASOs that inhibit mRNA translation. Generally speaking, as known to the art, RNAi operates sequence specifically and post- transcriptionally by activating ribonucleases which, along with other enzymes and complexes, coordinately degrade the RNA after the original RNA target has been cut into smaller pieces while antisense oligonucleotides bind to their target nucleic acid via Watson-Crick base pairing, and inhibit or alter gene expression via steric hindrance, splicing alterations, initiation of target degradation, or other events.

[0138] As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer.

[0139] The terms "proliferative disorder" and "proliferative disease" refer to disorders associated with abnormal cell proliferation such as cancer.

[0140] In an aspect, "tumor" and "neoplasm" refer to any mass of tissue that result from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous) including pre- cancerous lesions.

[0141] In an aspect, "metastasis refers to the process by which a cancer spreads or transfers from the site of origin to other regions of the body with the development of a similar cancerous lesion at the new location. A "metastatic" or "metastasizing" cell is one that loses adhesive contacts with neighboring cells and migrates via the bloodstream or lymph from the primary site of disease to invade neighboring body structures.

[0142] The terms "cancer stem cell" or "tumor stem cell" or "solid tumor stem cell" are used interchangeably herein and refer to a population of cells from a solid tumor that: (1) have extensive proliferative capacity; (2) are capable of asymmetric cell division to generate one or more kinds of differentiated progeny with reduced proliferative or developmental potential; and (3) are capable of symmetric cell divisions for self-renewal or self-maintenance. These properties of "cancer stem cells" or "tumor stem cells" or "solid tumor stem cells" confer on those cancer stem cells the ability to form palpable tumors upon serial transplantation into an immunocompromised mouse compared to the majority of tumor cells that fail to form tumors. Cancer stem cells undergo self-renewal versus differentiation in a chaotic manner to form tumors with abnormal cell types that can change over time as mutations occur.

[0143] The terms "cancer cell" or "tumor cell" and grammatical equivalents refer to the total population of cells derived from a tumor including both non-tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells).

[0144] As used herein "delay" in the context of tumor growth refers to a prolongation of the time it takes for a tumor to reach a determined size or stage as a result of, for example, a disclosed therapeutic treatment.

[0145] As used herein "abrogate" in the context of tumor growth refers to the suppression or elimination of tumor development as a result of, for example, a disclosed therapeutic treatment.

[0146] As used herein "tumorigenic" refers to the functional features of a solid tumor stem cell including the properties of self-renewal (giving rise to additional tumorigenic cancer stem cells) and proliferation to generate all other tumor cells (giving rise to differentiated and thus non- tumorigenic tumor cells) that allow solid tumor stem cells to form a tumor.

[0147] As used herein, the "tumorigenicity" of a tumor refers to the ability of a random sample of cells from the tumor to form palpable tumors upon serial transplantation into immunocompromised mice.

[0148] As used herein, "lipid nanoparticles" or "LNPs" can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA-guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-di enoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z, 12Z)-octadeca-9, 12-di enoate) or another ionizable lipid. In an aspect, the term cationic and ionizable in the context of LNP lipids can be used interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0149] "Sequence identity" and "sequence similarity" can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as "substantially identical" or "essentially similar" when they are optimally aligned. For example, sequence similarity or identity can be determined by searching against databases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identity. Two proteins or two protein domains, or two nucleic acid sequences can have "substantial sequence identity" if the percentage sequence identity is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more, preferably 90%, 95%, 98%, 99% or more. Such sequences are also referred to as "variants" herein, e.g., other variants of a missing, deficient, and/or mutant protein or enzyme. It should be understood that sequence with substantial sequence identity do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3"- and/or 5"-side are 100% identical.

[0150] As used herein, "immune-modulating" refers to the ability of the one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to alter (modulate) one or more aspects of the immune system. The immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanisms involving lymphocytes, macrophages, and other antigen-presenting cells that regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells. [0151] As used herein, "immune modulator" refers to an agent that is capable of adjusting a given immune response to a desired level (e.g., as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine, cyclophosphamide, cyclosporine, deoxyspergualin, didemnin B, fluocinolone acetonide, folinic acid, ibuprofen, IL6 inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenous gamma globulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP -Rapamycin or ImmTOR), thalidomide, tocilizumab, tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti- CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti -IGF 1R antibodies, an IL2 mutein, a BTK inhibitor, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP -Rapamycin. In an aspect, an immune modulator can be administered by any suitable route of administration including, but not limited to, in utero, intra-CSF, intrathecally, intravenously, subcutaneously, transdermally, intradermally, intramuscularly, orally, transcutaneously, intraperitoneally (IP), or intravaginally. In an aspect, a disclosed immune modulator can be administered using a combination of routes. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of an immune modulator can be continuous or intermittent, and administration can comprise a combination of one or more routes.

[0152] As used herein, the term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

[0153] As used herein, the term "in combination" in the context of the administration of other therapies (e.g., other agents) includes the use of more than one therapy (e.g., drug therapy). Administration "in combination with" one or more further therapeutic agents includes simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the term "in combination" does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., one or more disclosed anti-mutant KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof) can be administered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy to a subject having or diagnosed with mutant KRAS-driven cancer.

[0154] Disclosed are the components to be used to prepare the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific claimed compositions and/or claimed methods.

B. KRAS Mutation-Driven Cancers

[0155] The KRAS gene is a member of the rat sarcoma viral oncogene family (RAS), which includes two other isoforms in humans: the Harvey and neuroblastoma rat sarcoma viral oncogenes (HRAS, NRAS). In 1982, Weinberg and Barbacid isolated a gene from human bladder cancer cell lines. Subsequently, this gene was identified as a human homologue of the RAS gene, named HRAS, located on the short arm of chromosome 11 (1 Ip 15.1—1 Ip 15.3). In the same year, another homologue was found in human lung cancer cells, called KRAS, located on the short arm of chromosome 12 (12pl 1.1- 12pl2.1). The last gene, called NRAS, is found in human neuroblastoma and is located on the short arm of chromosome 1 (Ip22-lp32).

[0156] RAS genes are evolutionarily conserved with similar structures and are composed of four exons distributed on the full length of approximately 30 kb DNA. The KRAS gene (Gene ID No. 3845; see also SEQ ID NO: 16 and NG_007524.2) encodes two highly related protein isoforms, KRAS-4B (NP_001356716.1 and NM_001369787) and KRAS-4A (NP_001356715. 1 and NM_001369786.1), which consist of 188 and 189 amino acids, respectively, due to different clipping of the fourth exon. The other two RAS proteins all contain 189 amino acids.

[0157] The term KRAS is generally referred to as KRAS-4B due to the high level of mRNA encoding KRAS-4B in cells. The crystal structure of RAS reveals six beta strands and five alpha helices, which form two major domains: a catalytic domain called the G domain and a hypervariable region (HVR). The G domain consists of three regions: switch I, switch II, and the P loop, which binds guanine nucleotides and activates signalling by interacting with effectors. The HVR comprises the CAAX motif related to membrane localization. From the perspective of function, RAS is a kind of membrane-bound regulatory protein (G protein) binding guanine nucleotide belonging to the family of guanosine triphosphatases (GTPases). RAS functions as a guanosine diphosphate (GDP)/triphosphate (GTP) binary switch, which controls important signal transduction from activated membrane receptors to intracellular molecules. The binary switch is mainly determined by two kinds of regulatory proteins: guanine nucleotide exchange factors (GEFs) such as son of sevenless (SOS) and GTPase-activating proteins (GAPs) such as neurofibromin 1 (NF1). In the resting state, KRAS normally binds with GDP in an inactivated state due to the intrinsic GTPase activity of KRAS, which is able to hydrolyse GTP to GDP. When the cells receive the relevant stimuli, such as the interaction of EGF and EGFR, the KRAS-GDP complex appears to have a decreased affinity of KRAS with GDP in the presence of GEFs, and then GDP is replaced by GTP, which has a higher affinity and an approximately 10-fold higher cellular concentration than GDP. KRAS-GTP binding acquires an altered conformation in switches I and II of the G domain, and then KRAS is activated and binds to its downstream molecules as a monomer or dimer to mediate a series of signalling cascades. In contrast, GAPs promote the binding between GDP and KRAS by enhancing the GTPase activity of KRAS, thus maintaining the inactive state of KRAS.

[0158] KRAS mutations are common in a variety of cancers. For example, a disclosed mutant KRAS can comprise KRAS^G12A, KRAS^G12C, KRAS^G12D, KRAS^G12R, KRAS^G12S, KRAS^G12V, KRAS^G12X, KRAS^G13C, KRAS^G13D, KRAS^G13X, KRAS⁵⁶¹¹¹, KRAS^^, KRAS^Q61K, KRAS^Q61R, KRAS^Q61X, KRAS^A146T, KRAS^A146V, KRAS^A146X, or any combination thereof.

[0159] KRAS mutations have been identified in about 45% of CRC cases in the United States and about 49% of CRC cases in China; about 90% of pancreatic ductal adenocarcinoma (PDAC) in the United States, and abou t89% in China; and about 35% of lung adenocarcinomas (LU AD, a subtype of non-small-cell lung cancer) in the United States, and about 13% in China. KRAS has two isomers, KRAS4A and KRAS4B, that are generated by selective splicing of the KRAS gene. The mutant subtypes of KRAS are mainly classified as KRAS (G12D), KRAS (G12V), KRAS (G12C), KRAS (G13D), KRAS (G12R), and KRAS (G12A) mutations or KRAS wild-type amplification. The distribution of KRAS mutations varies in different human cancers, with KRAS (G12C) mutation in 41% of LU AD, whereas KRAS (G12D) and KRAS (G12V) are the two most common alleles in CRC and PDAC. Notably, other KRAS alleles such as G12R are limited in PDAC. Indeed, although the tumor type is driven by KRAS mutations, its codons and the frequency of mutations vary by tissue. Genetic alteration of G12 or G13 destroys the stability of the arginine residue hydrolysis transition state.

C. Compositions

Antibodies

[0160] Disclosed herein are anti-mutant KRAS antibodies. In an aspect, a disclosed anti-mutant KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti -mutant KRAS. In an aspect, a disclosed anti -mutant KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti-mutant KRAS, wherein the means for biding PIGR can comprise a PIGR peptide binding domain for IgG antibodies or a J chain for IgA antibodies.

IgG Backbone

[0161] Disclosed herein is an anti-mutant KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS.

[0162] Disclosed herein is an antibody recognizing the GTP -bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS. [0163] In an aspect, a disclosed anti-mutant KRAS antibody can slow or can prevent tumor growth. In an aspect, a disclosed mutant KRAS can comprise KRAS^G12A, KRAS^G12C, KRAS^G12D, KRAS^G12R, KRAS^G12S, KRAS^G12V, KRAS^G12X, KRAS^G13C, KRAS^G13D, KRAS^G13X, KRAS⁵⁶¹¹¹, KRAS^Q61L, KRAS^, KRAS^Q61R, I<RAS^(X,I , KRAS^A146T, KRAS^A146V, KRAS^A146X, or any combination thereof.

[0164] In an aspect, a disclosed anti-mutant KRAS can comprise (i) a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and (ii) a variable heavy chain region (VH) comprising 3 CDRs and a constant heavy chain region, wherein the VH is linked to the constant heavy chain region, and wherein the constant heavy chain region is linked to the PIGR biding domain.

[0165] In an aspect of a disclosed anti -mutant KRAS antibody, each CDR in the VL can comprise the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

[0166] In an aspect of a disclosed anti-mutant KRAS antibody, each CDR in the VL can comprise the sequence set forth in any one of SEQ ID NO: 02, SEQ ID NO: 03, SEQ ID NO: 04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

[0167] In an aspect of a disclosed anti-mutant KRAS antibody, a CDR in the VL can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111. [0168] In an aspect of a disclosed anti-mutant KRAS antibody, a CDR in the VL can comprise a sequence having between about 60% and about 70% identity or between about 70% and about 80% identity to the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

[0169] In an aspect of a disclosed anti -mutant KRAS antibody, a CDR in the VH can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence in any one of SEQ ID NO:02, SEQ ID NO:03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

[0170] In an aspect of a disclosed anti-mutant KRAS antibody, a CDR in the VH can comprise a sequence having between about 60% and about 70% identity or between about 70% and about 80% identity to the sequence set forth in any one of SEQ ID NO:02, SEQ ID NO:03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

[0171] In an aspect, a disclosed anti-mutant KRAS antibody can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO: 06, SEQ ID NO: 07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ IDNO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 124, SEQ ID NO: 125, and SEQ ID NO: 126. In an aspect, a disclosed anti -mutant KRAS antibody can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO: 02, SEQ ID NO: 03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107. In an aspect, choosing the amino acid substitutions for a disclosed CDR can be informed by Gonzalez-Munoz et al. (2012) MAbs. 4(6):664-672, which is incorporated herein in its entirety for its teaching of tailoring amino acid diversity for the evolution of antibody affinity.

[0172] In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 06, a CDR having the sequence set forth in SEQ ID NO:07, and a CDR having the sequence set forth in SEQ ID NO:08. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

[0173] In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO:04. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:97, a CDR having the sequence set forth in SEQ ID NO:98, and a CDR having the sequence set forth in SEQ ID NO:99. In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprises a CDR having the sequence set forth in SEQ ID NO: 06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO:08; and a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO:04.

[0174] In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:05, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:OL

[0175] In an aspect of a disclosed anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:05, and a disclosed VH, the constant heavy chain region, a GS- based spacer, and a PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO: 114.

[0176] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17; and a disclosed VH comprises a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13.

[0177] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO: 14, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO: 10.

[0178] In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21; and a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25.

[0179] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:22, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO: 18.

[0180] In an aspect of an anti -mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 97, a CDR having the sequence set forth in SEQ ID NO: 98, and a CDR having the sequence set forth in SEQ ID NO:99; and a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103.

[0181] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO: 100, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO: 96.

[0182] In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107; and a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

[0183] In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO: 108, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO: 104. [0184] In an aspect of an anti-mutant KRAS antibody, a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR binding domain can comprise the sequence set forth in SEQ ID NO:26, SEQ ID NO:37 or SEQ ID NO: 50, and a disclosed VL can comprise the sequence set forth in SEQ ID NO:33, SEQ ID NO:44 or SEQ ID NO:57.

[0185] In an aspect of an anti -mutant KRAS antibody, a disclosed CDR in a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:38, SEQ ID NO:39, SEQ IDNO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:51, SEQ ID NO:52, SEQ IDNO:53, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56.

[0186] In an aspect of an anti-mutant KRAS antibody, a disclosed CDR in a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ IDNO:49, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO: 124, SEQ ID NO: 125, and SEQ ID NO: 126.

[0187] In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:34, a CDR having the sequence set forth in SEQ ID NO:35, and a CDR having the sequence set forth in SEQ ID NO:36. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 124, a CDR having the sequence set forth in SEQ ID NO: 125, and a CDR having the sequence set forth in SEQ ID NO: 126. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:45 or SEQ ID NO:46, a CDR having the sequence set forth in SEQ ID NO:47 or SEQ ID NO:48, and a CDR having the sequence set forth in SEQ ID NO:49. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:58 or SEQ ID NO:59, a CDR having the sequence set forth in SEQ ID NO:60 or SEQ ID NO:61, and a CDR having the sequence set forth in SEQ ID NO:62. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:27 or SEQ ID NO:28, a CDR having the sequence set forth in SEQ ID NO:29 or SEQ ID NO:30, and a CDR having the sequence set forth in SEQ ID NO:31 or SEQ ID NO: 32. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39, a CDR having the sequence set forth in SEQ ID NO:40 or SEQ ID NO:41, and a CDR having the sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:51 or SEQ ID NO:52, a CDR having the sequence set forth in SEQ ID NO:53 or SEQ ID NO:54, and a CDR having the sequence set forth in SEQ ID NO: 55.

[0188] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:33, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:26. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:44, and a disclosed VH region, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:37. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:57, and a disclosed VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:50.

[0189] In an aspect of an anti -mutant KRAS antibody, each CDR in a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO: 85, and SEQ ID NO:86. In an aspect of an anti-mutant KRAS antibody, each CDR in a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

[0190] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise 3 complementarity determining regions (CDRs), and a disclosed VH can comprise 3 CDRs, wherein the VH is linked to a constant heavy chain region.

[0191] In an aspect of an anti -mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:67, SEQ ID NO:75; or SEQ ID NO:83; and a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in SEQ ID NO:63, SEQ ID NO:71, or SEQ ID NO:79.

[0192] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:05, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:OL

[0193] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 14, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 10.

[0194] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:22, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 18. [0195] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 100, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:96.

[0196] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 108, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 104.

[0197] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:33, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:26.

[0198] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:44, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:37.

[0199] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:57, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:50.

[0200] In an aspect, a disclosed anti-mutant KRAS antibody can bind intracellular KRAS and can promote the expulsion of the mutant KRAS from the cytoplasm of the cell.

[0201] In an aspect, a disclosed anti-mutant KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti-mutant KRAS. In an aspect, a disclosed anti-mutant KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti -mutant KRAS, wherein the means for biding PIGR can comprise a PIGR peptide binding domain for IgG antibodies.

[0202] In an aspect, a disclosed spacer can be a GS-based spacer sequence (such as, for example, GGGGS - SEQ ID NO:95). In an aspect, a disclosed spacer can be a rigid spacer or a flexible spacer. In an aspect, a disclosed spacer can be a glycine-serine linker or an aspartic acid-proline spacer. By adjusting the copy number "n" of a flexible linker, the length of a GS-based linker can be optimized to achieve appropriate separation of the functional domains, maintain necessary inter-domain interactions, and allow for proper folding of the fusion proteins. In an aspect, a disclosed rigid linker.

[0203] Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising any disclosed VL including, for example, those listed in Table 3. Disclosed herein is an antimutant KRAS antibody having an IgG backbone comprising any disclosed VH including, for example, those listed in Table 2. Disclosed herein is an anti-mutant KRAS antibody having an IgGbackbone comprising a VL comprising any disclosed CDR including, for example, those listed in Table 1. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VH comprising any disclosed CDR including, for example, those listed in Table 1. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a combination of any disclosed VL and any disclosed VH, such as, for example, those disclosed in Table 2 and Table 3. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VL and a VH, each comprising a combination of any disclosed CDRs such as, for example, those disclosed in Table 1.

[0204] In an aspect of an anti-mutant KRAS antibody, a disclosed constant heavy chain region can be linked to one or more disclosed PIGR biding domains. In an aspect of an anti -mutant KRAS antibody, a disclosed constant heavy chain region can be linked to a disclosed PIGR binding domain by a spacer.

[0205] In an aspect of an anti-mutant KRAS antibody, the binding of the one or more PIGR binding domains to PIGR on a cell triggers transcytosis of the disclosed antibody into the cell.

[0206] In an aspect of an anti-mutant KRAS antibody, a disclosed IgG backbone can comprise an IgGl backbone, an IgG2 backbone, an IgG3 backbone, or an IgG4 backbone.

[0207] In an aspect, a disclosed anti-mutant KRAS antibody can be used in a disclosed method. In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used in a disclosed method. In an aspect, a disclosed anti -mutant KRAS antibody can be used in a disclosed method of treating a subject having cancer. In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used in a disclosed method of treating a subject having cancer. In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used in a method of treating a subject having pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

[0208] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can induce PIGR mediated transcytosis in one or more cells including, for example, one or more cancer cells and/or one or more tumor cells.

[0209] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used to (i) prevent and/or decrease the risk of developing metastases, (ii) prolong the survival of the subject, (iii) enhance and/or improve the subject's quality of life, (iv) reduce and/or minimize the likelihood of surgical intervention, (v) reduce and/or decrease the size of one or more tumors in the subject, (vi) eliminate one or more tumors in the subject, (vii) improve and/or restore normal metabolism of one or more organ systems in the subject, (viii) restore and/or improve one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation are, or (ix) any combination thereof.

[0210] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used to prevent an undesired physiological change, disease, pathological condition, or disorder from occurring in the subject having cancer. In an aspect, a disclosed anti -mutant KRAS antibody comprising an IgG backbone can be used to inhibit a physiological change, disease, pathological condition, or disorder, z.e., arresting its development, in the subject. In an aspect, a disclosed antimutant KRAS antibody comprising an IgG backbone can be used to relieve a physiological change, disease, pathological condition, or disorder, z.e., causing regression of the disease, in the subject.

[0211] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used to treat and/or prevent cancer, to prolong the survival of the subject, to prevent and/or decrease metastases, to protect the subject from metastasis, to reduce the risk of developing metastases, to increase the subject's survivability, to increase the length of time before metastasis, to reduce the likelihood of surgical intervention, to reduce the need for administration of one or more additional therapeutic agents or regimens, to reduce the size of one or more tumors in the subject, to reduce the size of one or more tumors in one or more organs in the subject, to eliminate one or more tumors in the subject, to reduce and/or eliminate the prevalence of one or more genomic aberrations, to restore normal metabolism of one or more organ systems in the subject, to restore one or more aspects of cellular homeostasis, cellular functionality, and/or metabolic dysregulation in a subject, to reduce and/or inhibit aberrant angiogenesis and/or vasculogenesis in one or more tissues and/or organs of the subject, or any combination thereof.

[0212] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used to improve and/or can be used to enhance the quality of the subject's life when compared to a pre-treatment level. In an aspect, a disclosed anti -mutant KRAS antibody comprising an IgG backbone can be used to improve the subject's quality of life by at least 50% when compared to the subject's pre-treatment quality of life. In an aspect, a disclosed anti -mutant KRAS antibody comprising an IgG backbone can be used to diminish and/or decrease one or more symptoms associated with and/or related to the subject's cancer.

[0213] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used with one or more additional therapeutic agents. In an aspect, a disclosed therapeutic agent can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be used with one or more targeted therapies.

[0214] In an aspect, a disclosed anti-mutant KRAS antibody comprising an IgG backbone can be included in a disclosed pharmaceutical formulation (discussed infra). In an aspect, a disclosed anti -mutant KRAS antibody comprising an IgG backbone can be administered to a subject having cancer in one or more routes of administration (discussed infra).

[0215] In an aspect, a disclosed PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:09 (QRNPKLKLIRRHPTLRIPPI). In an aspect, a disclosed PIGR peptide binding domain can comprise any binding domains that can bind to the extracellular domain of PIGR or a portion thereof. In an aspect, a disclosed PIGR peptide binding domain can comprise any binding domains that can bind to the extracellular domain of PIGR or a portion thereof, and is less immunogenic than a PIGR binding domain comprising the sequence set forth in SEQ ID NO:09. In an aspect, a disclosed PIGR peptide binding domain can comprise any peptide binding domains that can bind to one or more of DI, D2, D3, D4, and D5 of the extracellular domain of PIGR or a portion thereof.

[0216] In an aspect, one or more disclosed anti-mutant KRAS antibodies having an IgG backbone and/or a pharmaceutical formulation thereof can be subjected to one or more validating and/or characterizing steps and/or protocols. For example, in an aspect, validating and/or characterizing one or more disclosed anti-mutant KRAS antibodies having an IgG backbone and/or a pharmaceutical formulation thereof can comprise measuring, ascertaining, and/ or determining the purity and/or efficacy of the one or more disclosed anti-mutant KRAS antibodies having an IgG backbone and/or a pharmaceutical formulation thereof.

TABLE 1 - CDRs for VH and CDRs for VL

TABLE 2 - Exemplary VH Sequences of Anti-Mutant KRAS Antibody

TABLE 3 - Exemplary VL Sequences of Anti-Mutant KRAS Antibody

Dimeric IgA Backbone

[0217] Disclosed herein is anti-mutant KRAS antibody comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP -bound active form of KRAS.

[0218] Disclosed herein is antibody recognizing the GTP -bound active conformation of mutant KRAS comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP- bound active form of KRAS.

[0219] In an aspect, a disclosed anti -mutant KRAS antibody can slow or can prevent tumor growth. In an aspect, a disclosed mutant KRAS can comprise KRAS^G12A, KRAS^G12C, KRAS^G12D, KRAS^G12R, KRAS^G12S, KRAS^G12V, KRAS^G12X, KRAS^G13C, KRAS^G13D, KRAS^G13X, KRAS⁵⁶¹¹¹, KRAS^Q61L, KRAS^, KRAS^Q61R, I<RAS^(X,I , KRAS^A146T, KRAS^A146V, KRAS^A146X, or any combination thereof.

[0220] In an aspect of an anti-mutant KRAS antibody, each CDR in a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86.

[0221] In an aspect of an anti-mutant KRAS antibody, each CDR in a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

[0222] In an aspect of an anti-mutant KRAS antibody, each CDR in a disclosed VL can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86.

[0223] In an aspect of an anti-mutant KRAS antibody, each CDR in a disclosed VH can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

[0224] In an aspect, a disclosed anti-mutant KRAS antibody can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ IDNO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 124, SEQ ID NO: 125, and SEQ ID NO: 126. In an aspect, a disclosed anti-mutant KRAS antibody can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO: 02, SEQ ID NO: 03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107. In an aspect, choosing the amino acid substitutions for a disclosed CDR can be informed by Gonzalez-Munoz et al. (2012) MAbs. 4(6):664-672, which is incorporated herein in its entirety for its teaching of tailoring amino acid diversity for the evolution of antibody affinity.

[0225] In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 68, a CDR having the sequence set forth in SEQ ID NO: 69, and a CDR having the sequence set forth in SEQ ID NO:70. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:76, a CDR having the sequence set forth in SEQ ID NO:77, and a CDR having the sequence set forth in SEQ ID NO:78. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 84, a CDR having the sequence set forth in SEQ ID NO:85, and a CDR having the sequence set forth in SEQ ID NO:86. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:64, a CDR having the sequence set forth in SEQ ID NO:65, and a CDR having the sequence set forth in SEQ ID NO:66. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:72, a CDR having the sequence set forth in SEQ ID NO:73, and a CDR having the sequence set forth in SEQ ID NO:74. In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:80, a CDR having the sequence set forth in SEQ ID NO:81, and a CDR having the sequence set forth in SEQ ID NO:82. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:67; and a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in SEQ ID NO:63. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:75; and a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in SEQ ID NO:71. In an aspect of an anti-mutant KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:83; and a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in SEQ ID NO:79.

[0226] In an aspect of an anti-mutant KRAS antibody, a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 119; and a disclosed VL can comprise the sequence set forth in SEQ ID NO:05, SEQ ID NO: 14, SEQ ID NO:22, SEQ ID NO: 100, and SEQ ID NO: 108.

[0227] In an aspect of an anti -mutant KRAS antibody, a CDR in a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

[0228] In an aspect of an anti-mutant KRAS antibody, a CDR in a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO: 02, SEQ ID NO: 03, SEQ ID NO: 04, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ IDNO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, and SEQ ID NO: 120.

[0229] In an aspect, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO: 08. In an aspect, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17. In an aspect, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25. In an aspect, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103. In an aspect, a disclosed VL can comprise a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

[0230] In an aspect, a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in any one of SEQ ID NO: 121, SEQ ID NO: 122, and SEQ ID NO: 123.

[0231] In an aspect, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO:04. In an aspect, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13. In an aspect, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21. In an aspect, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 97, a CDR having the sequence set forth in SEQ ID NO: 98, and a CDR having the sequence set forth in SEQ ID NO:99. In an aspect, a disclosed VH can comprise a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107.

[0232] In an aspect, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:05, SEQ ID NO: 14, SEQ ID NO:22, SEQ ID NO:33, SEQ ID NO:44, SEQ ID NO:57, SEQ IDNO:67, SEQ ID NO:75, SEQ ID NO:83, SEQ ID NO: 100, and SEQ ID NO: 108; and a disclosed VH linked to the constant heavy chain region can comprise the sequence set forth in any one of SEQ ID NO:63, SEQ ID NO:71, SEQ ID NO:79. SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119. SEQ ID NO: 121, SEQ ID NO: 122, and SEQ ID NO: 123.

[0233] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 67, and (ii) a VH having the sequence set forth in SEQ ID NO: 63. [0234] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO: 75, and (ii) a VH having the sequence set forth in SEQ ID NO:71. [0235] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:83, and (ii) a VH having the sequence set forth in SEQ ID NO:79. [0236] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:67, SEQ ID NO:75, or SEQ ID NO:83, and (ii) a VH having the sequence set forth in any one of SEQ ID NO: 115 - SEQ ID NO: 119.

[0237] Disclosed herein is an anti-mutant KRAS antibody, comprising: (i) a VL having the sequence set forth in SEQ ID NO:67, SEQ ID NO:75, or SEQ ID NO:83, and (ii) a VH having the sequence set forth in any one of SEQ ID NO: 121, SEQ ID NO: 122, or SEQ ID NO: 123.

[0238] In an aspect, a first disclosed monomer can be connected to a second disclosed monomer via a j chain. In an aspect, a disclosed ] chain can comprise the sequence set forth in SEQ ID NOVO or a fragment thereof. In an aspect, a disclosed] chain can comprise the sequence set forth in SEQ ID NO:94 or a fragment thereof. The human JCHAIN gene (NCBI gene ID: 3512) is located on the q 13.3 region of chromosome 4. With a total of 4 exons, the human JCHAIN gene spans about 9.8 kb. In an aspect, j chain can mediate the polymerization of IgA. In an aspect, J chain can be involved in the recognition and binding of IgA by PIGR. In an aspect, J chain can be recognized by PIGR, leading to the transcytosis of a disclosed anti-mutant KRAS antibody comprising a dlgA backbone.

[0239] In an aspect, a disclosed anti-mutant KRAS antibody can bind intracellular KRAS and can promote the expulsion of the mutant KRAS from the cytoplasm of the cell.

[0240] In an aspect, a disclosed anti-mutant KRAS antibody having a dimeric IgA backbone can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti-mutant KRAS. In an aspect, a disclosed anti-mutant KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of anti-mutant KRAS, wherein the means for biding PIGR can comprise a J chain for IgA antibodies.

[0241] In an aspect, a disclosed anti -mutant KRAS antibody having a dimeric IgA backbone can comprise disclosed PIGR peptide binding domain having the sequence set forth in SEQ ID NO:09 or a fragment thereof. In an aspect, a disclosed PIGR peptide binding domain can comprise any binding domains that can bind to the extracellular domain of PIGR or a portion thereof. In an aspect, a disclosed PIGR peptide binding domain can comprise any binding domains that can bind to the extracellular domain of PIGR or a portion thereof, and is less immunogenic than a PIGR binding domain comprising the sequence set forth in SEQ ID NO: 09. In an aspect, a disclosed PIGR peptide binding domain can comprise any peptide binding domains that can bind to one or more of DI, D2, D3, D4, and D5 of the extracellular domain of PIGR or a portion thereof.

[0242] In an aspect, a disclosed spacer can be a GS-based spacer sequence (such as, for example, GGGGS - SEQ ID NO:95). In an aspect, a disclosed spacer can be a rigid spacer or a flexible spacer. In an aspect, a disclosed spacer can be a glycine-serine linker or an aspartic acid-proline spacer. By adjusting the copy number "n" of a flexible linker, the length of a GS-based linker can be optimized to achieve appropriate separation of the functional domains, maintain necessary inter-domain interactions, and allow for proper folding of the fusion proteins. In an aspect, a disclosed rigid linker.

[0243] Disclosed herein is an anti-mutant KRAS antibody having a dimeric IgA backbone comprising any disclosed VL including, for example, those listed in Table 3. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising any disclosed VH including, for example, those listed in Table 2. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VL comprising any disclosed CDR including, for example, those listed in Table 1. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VH comprising any disclosed CDR including, for example, those listed in Table 1. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a combination of any disclosed VL and any disclosed VH, such as, for example, those disclosed in Table 2 and Table 3. Disclosed herein is an anti-mutant KRAS antibody having an IgG backbone comprising a VL and a VH, each comprising a combination of any disclosed CDRs such as, for example, those disclosed in Table 1.

[0244] In an aspect of an anti-mutant KRAS antibody, a disclosed constant heavy chain region can be linked to one or more disclosed PIGR biding domains. In an aspect of an anti -mutant KRAS antibody, a disclosed constant heavy chain region can be linked to a disclosed PIGR binding domain by a spacer. In an aspect of an anti-mutant KRAS antibody, the binding of the one or more PIGR binding domains to PIGR on a cell triggers transcytosis of the disclosed antibody into the cell.

[0245] In an aspect, a disclosed spacer can be a GS-based spacer sequence (such as, for example, GGGGS - SEQ ID NO:95). In an aspect, a disclosed spacer can be a rigid spacer or a flexible spacer. In an aspect, a disclosed spacer can be a glycine-serine linker or an aspartic acid-proline spacer. By adjusting the copy number "n" of a flexible linker, the length of a GS-based linker can be optimized to achieve appropriate separation of the functional domains, maintain necessary inter-domain interactions, and allow for proper folding of the fusion proteins. In an aspect, a disclosed rigid linker.

[0246] In an aspect, a disclosed anti-mutant KRAS antibody can be used in a disclosed method. In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used in a disclosed method. In an aspect, a disclosed anti-mutant KRAS antibody can be used in a disclosed method of treating a subj ect having cancer. In an aspect, a disclosed anti -mutant KRAS antibody comprising a dimeric IgA backbone can be used in a disclosed method of treating a subject having cancer. In an aspect, a disclosed anti -mutant KRAS antibody comprising a dimeric IgA backbone can be used in a method of treating a subject having pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

[0247] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can induce PIGR mediated transcytosis in one or more cells including, for example, one or more cancer cells and/or one or more tumor cells.

[0248] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used to (i) prevent and/or decrease the risk of developing metastases, (ii) prolong the survival of the subject, (iii) enhance and/or improve the subject's quality of life, (iv) reduce and/or minimize the likelihood of surgical intervention, (v) reduce and/or decrease the size of one or more tumors in the subject, (vi) eliminate one or more tumors in the subject, (vii) improve and/or restore normal metabolism of one or more organ systems in the subject, (viii) restore and/or improve one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation are, or (ix) any combination thereof.

[0249] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used to prevent an undesired physiological change, disease, pathological condition, or disorder from occurring in the subject having cancer. In an aspect, a disclosed anti -mutant KRAS antibody comprising a dimeric IgA backbone can be used to inhibit a physiological change, disease, pathological condition, or disorder, z.e., arresting its development, in the subject. In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used to relieve a physiological change, disease, pathological condition, or disorder, z.e., causing regression of the disease, in the subject.

[0250] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used to treat and/or prevent cancer, to prolong the survival of the subject, to prevent and/or decrease metastases, to protect the subject from metastasis, to reduce the risk of developing metastases, to increase the subject's survivability, to increase the length of time before metastasis, to reduce the likelihood of surgical intervention, to reduce the need for administration of one or more additional therapeutic agents or regimens, to reduce the size of one or more tumors in the subject, to reduce the size of one or more tumors in one or more organs in the subject, to eliminate one or more tumors in the subject, to reduce and/or eliminate the prevalence of one or more genomic aberrations, to restore normal metabolism of one or more organ systems in the subject, to restore one or more aspects of cellular homeostasis, cellular functionality, and/or metabolic dysregulation in a subject, to reduce and/or inhibit aberrant angiogenesis and/or vasculogenesis in one or more tissues and/or organs of the subject, or any combination thereof.

[0251] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used to improve and/or can be used to enhance the quality of the subject's life when compared to a pre-treatment level. In an aspect, a disclosed anti -mutant KRAS antibody comprising a dimeric IgA backbone can be used to improve the subject's quality of life by at least 50% when compared to the subject's pre-treatment quality of life. In an aspect, a disclosed antimutant KRAS antibody comprising a dimeric IgA backbone can be used to diminish and/or decrease one or more symptoms associated with and/or related to the subject's cancer. [0252] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used with one or more additional therapeutic agents. In an aspect, a disclosed therapeutic agent can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be used with one or more targeted therapies.

[0253] In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be included in a disclosed pharmaceutical formulation (discussed infra). In an aspect, a disclosed anti-mutant KRAS antibody comprising a dimeric IgA backbone can be administered to a subject having cancer in one or more routes of administration (discussed infra).

[0254] In an aspect, one or more disclosed anti-mutant KRAS antibodies comprising a dimeric IgA backbone and/or a pharmaceutical formulation thereof can be subjected to one or more validating and/or characterizing steps and/or protocols. For example, in an aspect, validating and/or characterizing one or more disclosed anti-mutant KRAS antibodies comprising a dimeric IgA backbone and/or a pharmaceutical formulation thereof can comprise measuring, ascertaining, and/ or determining the purity and/or efficacy of the one or more disclosed anti-mutant KRAS antibodies comprising a dimeric IgA backbone and/or a pharmaceutical formulation thereof.

[0255] Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed VH. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed VL. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a VH listed in Table 2. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a VL listed in Table 3. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a VH listed in Table 2. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a VL listed in Table 3.

[0256] Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding the VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain set forth in SEQ ID NO:01, SEQ ID NO: 10, SEQ ID NO: 18, SEQ ID NO:96, SEQ ID NO: 104, SEQ ID NO:26, SEQ ID NO:37, or SEQ ID NO:50. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding the VH set forth in SEQ ID NO:63, SEQ ID NO:71, or SEQ ID NO:78.

[0257] Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding the VL set forth in SEQ ID NO:05, SEQ ID NO: 14, SEQ ID NO:22, SEQ ID NO: 100, SEQ ID NO: 108, SEQ ID NO:33, SEQ ID NO:44, or SEQ ID NO:57. Disclosed herein is an isolated nucleic acid molecule comprising a nucleic acid sequence encoding the VL set forth in SEQ ID NO:67, SEQ ID NO:75, or SEQ ID NO:83.

[0258] In an aspect, SEQ ID NO: 128 can encode the VH of SEQ ID NO:01. In an aspect, SEQ ID NO: 130 can encode the VH of SEQ ID NO:05. In an aspect, SEQ ID NO: 131 can encode the VH of SEQ ID NO: 10. In an aspect, SEQ ID NO: 132 can encode the VH of SEQ ID NO: 14. In an aspect, SEQ ID NO: 133 can encode the VH of SEQ ID NO: 18. In an aspect, SEQ ID NO: 134 can encode the VH of SEQ ID NO:22. In an aspect, SEQ ID NO: 135 can encode the VH of SEQ ID NO:96. In an aspect, SEQ ID NO: 136 can encode the VH of SEQ ID NO: 100. In an aspect, SEQ ID NO: 137 can encode the VH of SEQ ID NO: 104. In an aspect, SEQ ID NO: 138 can encode the VH of SEQ ID NO: 108. In an aspect, SEQ ID NO: 139 can encode the VH of SEQ ID NO:26. In an aspect, SEQ ID NO: 140 can encode the VH of SEQ ID NO:33. In an aspect, SEQ ID NO: 141 can encode the VH of SEQ ID NO:37. In an aspect, SEQ ID NO: 142 can encode the VH of SEQ ID NO:44. In an aspect, SEQ ID NO: 143 can encode the VH of SEQ ID NO:50. In an aspect, SEQ ID NO: 144 can encode the VH of SEQ ID NO: 57. In an aspect, SEQ ID NO: 145 can encode the VH of SEQ ID NO:63. In an aspect, SEQ ID NO: 146 can encode the VH of SEQ ID NO:67. In an aspect, SEQ ID NO: 147 can encode the VH of SEQ ID NO:71. In an aspect, SEQ ID NO: 148 can encode the VH of SEQ ID NO:75. In an aspect, SEQ ID NO: 149 can encode the VH of SEQ ID NO:79. In an aspect, SEQ ID NO: 150 can encode the VH of SEQ ID NO:83.

TABLE 6 - Exemplary Nucleic Acid Sequences _

[0259] Disclosed herein is a vector comprising a disclosed nucleic acid molecule. Disclosed herein is a vector comprising one or more nucleic acid molecules set forth in Table 6. Disclosed herein is a vector comprising an nucleic acid molecule encoding a disclosed anti-mutant KRAS antibody or a component thereof. Disclosed herein is a vector comprising a nucleic acid molecule encoding a VH set forth in Table 2. Disclosed herein is a vector comprising a nucleic acid molecule encoding a VL set forth in Table 3. Disclosed herein is a vector comprising the nucleic acid molecule set forth in one or more of SEQ ID NO: 129 - SEQ ID NO: 150. Vectors are known to the skilled person in the art and are discussed supra.

Pharmaceutical Formulations

[0260] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed antimutant KRAS antibody, and one or more pharmaceutically acceptable carriers and/or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more anti-mutant KRAS antibody comprising an IgG backbone, and one or more pharmaceutically acceptable carriers and/or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more antimutant KRAS antibody comprising a dimeric IgA backbone, and one or more pharmaceutically acceptable carriers and/or excipients. Disclosed herein is a pharmaceutical formulation comprising an anti-mutant KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0261] Disclosed herein is a pharmaceutical formulation comprising an antibody recognizing the GTP -bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0262] Disclosed herein is a pharmaceutical formulation comprising an anti-mutant KRAS antibody comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP- bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0263] Disclosed herein is a pharmaceutical formulation comprising an antibody recognizing the GTP -bound active conformation of mutant KRAS comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the antibody recognizes the GTP -bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0264] Disclosed herein is a pharmaceutical formulation comprising one or more anti-mutant KRAS antibodies comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the one or more antibodies recognize the GTP- bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0265] Disclosed herein is a pharmaceutical formulation comprising one or more anti-mutant KRAS antibodies recognizing the GTP -bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the one or more antibodies recognize the GTP -bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0266] Disclosed herein is a pharmaceutical formulation comprising one or more anti-mutant KRAS antibodies comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the one or more antibodies recognize the GTP -bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0267] Disclosed herein is a pharmaceutical formulation comprising one or more anti-mutant KRAS antibodies recognizing the GTP -bound active conformation of mutant KRAS comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together; and wherein the one or more antibodies recognize the GTP-bound active form of KRAS, and one or more pharmaceutically acceptable carriers and/or excipients.

[0268] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed nucleic acid molecules and one or more pharmaceutically acceptable carriers and/or excipients.

[0269] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed nucleic acid molecules set forth in Table 6 and one or more pharmaceutically acceptable carriers and/or excipients. Disclosed herein is a pharmaceutical formulation comprising a disclosed vector and one or more pharmaceutically acceptable carriers and/or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising one or more nucleic acid sequences as set forth in any one of SEQ ID NO: 129 - SEQ ID NO: 150 and one or more pharmaceutically acceptable carriers and/or excipients.

[0270] In an aspect, a disclosed pharmaceutical formulation can be administered to a subject in need thereof. In an aspect, a disclosed pharmaceutical formulation can be formulated for administration and/or can be administered via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intraarterial administration or administration through the hepatic portal vein (HPV). Administration of a disclosed pharmaceutical formulation can comprise administration directly into the CNS (e.g., intraparenchymal, intracerebroventricular, intrathecal cisternal, intrathecal (lumbar), deep gray matter delivery, convection- enhanced delivery to deep gray matter) or the PNS. Administration can be continuous or intermittent. Administration of a disclosed pharmaceutical formulation can comprise intra-tumoral administration.

[0271] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody can be used in a disclosed method. In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody can be used in a disclosed method of treating a subject having cancer.

[0272] In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed anti-mutant KRAS antibody comprising an IgG backbone or a dimeric IgA backbone. In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody comprising an IgG backbone or a dimeric IgA backbone can be used in a disclosed method of treating a subject having cancer.

[0273] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody comprising an IgG backbone or a dimeric IgA backbone can be used in a method of treating a subject having pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody comprising an IgG backbone or a dimeric IgA backbone in a method of treating a subj ect having a cancer characterized by one or more KRAS mutations and/or caused by one or more KRAS mutations.

[0274] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-mutant KRAS antibody comprising an IgG backbone can induce PIGR mediated transcytosis in one or more cells including, for example, one or more cancer cells and/or one or more tumor cells.

[0275] In an aspect, a disclosed pharmaceutical formulation can be used to (i) prevent and/or decrease the risk of developing metastases, (ii) prolong the survival of the subject, (iii) enhance and/or improve the subject's quality of life, (iv) reduce and/or minimize the likelihood of surgical intervention, (v) reduce and/or decrease the size of one or more tumors in the subj ect, (vi) eliminate one or more tumors in the subject, (vii) improve and/or restore normal metabolism of one or more organ systems in the subject, (viii) restore and/or improve one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation are, or (ix) any combination thereof. [0276] In an aspect, a disclosed pharmaceutical formulation can be used with one or more additional therapeutic agents. In an aspect, a disclosed pharmaceutical formulation comprising can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof.

[0277] In an aspect, a disclosed pharmaceutical formulation can be used with one or more targeted therapies.

[0278] In an aspect, a disclosed pharmaceutical formulation can be used to treat and/or prevent cancer, to prolong the survival of the subject, to prevent and/or decrease metastases, to protect the subject from metastasis, to reduce the risk of developing metastases, to increase the subject's survivability, to increase the length of time before metastasis, to reduce the likelihood of surgical intervention, to reduce the need for administration of one or more additional therapeutic agents or regimens, to reduce the size of one or more tumors in the subject, to reduce the size of one or more tumors in one or more organs in the subject, to eliminate one or more tumors in the subject, to reduce and/or eliminate the prevalence of one or more genomic aberrations, to restore normal metabolism of one or more organ systems in the subject, to restore one or more aspects of cellular homeostasis, cellular functionality, and/or metabolic dysregulation in a subject, to reduce and/or inhibit aberrant angiogenesis and/or vasculogenesis in one or more tissues and/or organs of the subject, or any combination thereof.

[0279] In an aspect, a disclosed pharmaceutical formulation can be used to improve and/or can be used to enhance the quality of the subject's life when compared to a pre-treatment level.

[0280] In an aspect, a disclosed pharmaceutical formulation can be used to improve the subject's quality of life by at least 50% when compared to the subj ect's pre-treatment quality of life.

[0281] In an aspect, a disclosed pharmaceutical formulation can be used to diminish and/or decrease one or more symptoms associated with and/or related to the subject's cancer.

[0282] In an aspect, a disclosed pharmaceutical formulation can be used to prevent an undesired physiological change, disease, pathological condition, or disorder from occurring in the subject having cancer. In an aspect, a disclosed pharmaceutical formulation can be used to inhibit a physiological change, disease, pathological condition, or disorder, z.e., arresting its development, in the subject. In an aspect, a disclosed pharmaceutical formulation can be used to relieve a physiological change, disease, pathological condition, or disorder, z.e., causing regression of the disease, in the subject.

[0283] In an aspect, one or more disclosed pharmaceutical formulations can be subjected to one or more validating and/or characterizing steps and/or protocols. For example, in an aspect, validating and/or characterizing one or more disclosed pharmaceutical formulations can comprise measuring, ascertaining, and/ or determining the purity and/or efficacy of the one or more disclosed pharmaceutical formulations.

D. Methods

[0284] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed antimutant KRAS antibody.

[0285] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:05, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:01.

[0286] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 05, and (ii) a VH, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 114.

[0287] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 14, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 10.

[0288] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:22, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 18.

[0289] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 100, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 96.

[0290] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti -mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 108, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 104.

[0291] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:33, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:26.

[0292] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:44, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO:37.

[0293] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO: 57, and (ii) a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain having the sequence set forth in SEQ ID NO: 50.

[0294] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:67, and (ii) a VH having the sequence set forth in SEQ ID NO:63.

[0295] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:75, and (ii) a VH having the sequence set forth in SEQ ID NO:71.

[0296] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the antibody comprises (i) a VL having the sequence set forth in SEQ ID NO:83, and (ii) a VH having the sequence set forth in SEQ ID NO:79.

[0297] Disclosed herein is a method for treating a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-mutant KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. [0298] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more disclosed anti-mutant KRAS antibodies.

[0299] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0300] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the anti-mutant KRAS antibody having an IgG backbone comprise any VL listed in Table 3 and any VH listed in Table 2.

[0301] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-mutant KRAS antibody, wherein the anti-mutant KRAS antibody having a dimeric IgA backbone comprise any VL listed in Table 3 and any VH listed in Table 2. In an aspect of a disclosed method, an anti-mutant KRAS antibody having an IgG backbone can comprise any disclosed VL including, for example, those listed in Table 3. In an aspect of a disclosed method, an anti-mutant KRAS antibody having an IgG backbone can comprise any disclosed VH including, for example, those listed in Table 2.

[0302] In an aspect of a disclosed method, an anti-mutant KRAS antibody having an IgGbackbone comprising a VL can comprise any disclosed CDR including, for example, those listed in Table 3. In an aspect of a disclosed method, an anti-mutant KRAS antibody having an IgG backbone can comprising a VH can comprise any disclosed CDR including, for example, those listed in Table 2. In an aspect of a disclosed method, an anti-mutant KRAS antibody having an IgG backbone can comprise a combination of any disclosed VL (e.g., Table 3) and any disclosed VH (e.g., Table 2).

[0303] In an aspect, a disclosed cancer can be a KRAS mutation driven cancer. In an aspect, a disclosed cancer can be characterized as a mutant KRAS related and/or mutant KRAS adjacent cancer. In an aspect, a disclosed cancer can be characterized by cells expressing PIGR.

[0304] In an aspect, cancer can be pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

[0305] In an aspect, following the administering step, PIGR mediated transcytosis can be induced. [0306] In an aspect, a disclosed method can further comprise administering to the subject one or more additional anti-cancer therapies. In an aspect, a disclosed anti -cancer therapy can comprise endocrine therapy, radiotherapy, hormone therapy, gene therapy, thermal therapy, ultrasound therapy, or any combination thereof. In an aspect, a disclosed anti-cancer therapy can comprise one or more chemotherapeutic agents. In an aspect, a disclosed chemotherapeutic agent can comprise an anthracycline, a vinca alkaloid, an alkylating agent, an immune cell antibody, an antimetabolite, a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor, an immunomodulator, or any combination thereof. In an aspect, a disclosed chemotherapeutic agent can comprise 5 -fluorouracil (Adrucil, Efudex), 6-mercaptopurine (Purinethol), 6-thioguanine, aclarubicin or aclacinomycin A, alemtuzamab (Lemtrada), anastrozole (Arimidex), bicalutamide (Casodex), bleomycin sulfate (Blenoxane), bortezomib (Velcade), busulfan (Myleran), busulfan injection (Busulfex), capecitabine (Xeloda), carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), Cosmegan, cyclophosphamide (Cytoxan or Neosar), cyclophosphamide, cytarabine liposome injection (DepoCyt), cytarabine, cytosine arabinoside (Cytosar-U), dacarbazine (DTIC- Dome), dactinomycin (Cosmegen), daunorubicin citrate liposome injection (DaunoXome), daunorubicin hydrochloride (Cerubidine), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin, Rubex), etoposide (Vepesid), fludarabine phosphate (Fludara), flutamide (Eulexin), folic acid antagonists, gemcitabine (difluorodeoxycitidine), gemtuzumab, gliotoxin, hydroxyurea (Hydrea), Idarubicin (Idamycin), ifosfamide (IFEX), ifosfamide, irinotecan (Camptosar), L-asparaginase (ELSPAR), lenalidomide), leucovorin calcium, melphalan (Alkeran), melphalan, methotrexate (Fol ex), mitoxantrone (Novantrone), mylotarg, N4- pentoxy carbonyl -5 deoxy-5-fluorocytidine, nab-paclitaxel (Abraxane), paclitaxel (Taxol), pentostatin, phoenix (Yttrium90/MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel), purine analogs and adenosine deaminase inhibitors (fludarabine), pyrimidine analogs, rituximab, tamoxifen citrate (Nolvadex), temozolomide), teniposide (Vumon), tezacitibine, thalidomide or a thalidomide derivative, thiotepa, tirapazamine (Tirazone), topotecan hydrochloride for injection (Hycamptin), tositumomab), vinblastine (Velban), vinblastine, vincristine (Oncovin), vindesine, vinorelbine (Navelbine), or any combination thereof.

[0307] In an aspect, following the administering step, (i) the risk of developing metastases can be prevented and/or decreased; (ii) the survival of the subject can be prolonged; (iii) the subject's quality of life can be enhanced and/or improved; (iv) the likelihood of surgical intervention can be reduced and/or minimized; (v) preventing and/or delaying recurrence of the cancer; (vi) the size of one or more tumors in the subject can be reduced and/or decreased; (vii) one or more tumors in the subject can be eliminated; (viii) extending and/or prolonging disease-free or tumor-free survival time; (ix) increasing and/or lengthening overall survival time; (x) reducing and/or minimizing the frequency of treatment; (xi) relieving and/or ameliorating one or more symptoms of the cancer; (xii) reducing and/or decreasing tumor burden, (ix) preventing and/or facilitating surgical intervention; (xiii) normal metabolism of one or more organ systems in the subject can be improved and/or restored, (xiv) one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation can be restored and/or improved, or (xv) any combination thereof.

[0308] In an aspect of a disclosed method, administering one or more disclosed anti -mutant KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosed antimutant KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed composition comprising one or more disclosed anti-mutant KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses).

[0309] In an aspect, a therapeutically effective amount of a disclosed anti-mutant KRAS antibody can comprise about 1 ng/kg body weight/day to about 100 ng/kg body weight/day, about 10 ng/kg body weight/day to about 1 pg/kg body, about 100 ng/kg body weight/day to about 10 pg/kg body, about 1 pg/kg body weight/day to about 100 pg/kg body, about 10 pg/kg body weight/day to about 1 mg/kg body, about 100 pg/kg body weight/day to about 10 mg/kg body, or about 1 mg/kg body weight/day to about 100 mg/kg body weight/day. In an aspect, a therapeutically effective amount of a disclosed anti-mutant KRAS antibody can comprise about 10 mg/kg body weight/day, about 20 mg/kg body weight/day, about 30 mg/kg body weight/day, about 40 mg/kg body weight/day, about 50 mg/kg body weight/day, about 60 mg/kg body weight/day, about 70 mg/kg body weight/day, about 80 mg/kg body weight/day, about 90 mg/kg body weight/day, or about 100 mg/kg body weight/day.

[0310] Disclosed herein is a method for treating cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-mutant KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies.

[0311] In an aspect, a disclosed subject has already received or is actively receiving one or more disclosed targeted therapies. In an aspect, a subject is treatment-naive.

[0312] Disclosed herein is a method for reducing metastases in a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-mutant KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and/or molecular response to treatment regimen, and wherein metastases are prevented and/or decreased.

[0313] Disclosed herein is a method for reducing metastases in a subject having, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-mutant KRAS antibodies, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and/or molecular response to treatment regimen, and wherein metastases are prevented and/or decreased.

[0314] In an aspect of a disclosed method of treating and/or preventing cancer, administering a disclosed treatment regimen can comprise intravenous administration. In an aspect, a disclosed treatment regimen can be administered to a subject intravenously using, for example, a dualchannel infusion pump or two single channel pumps and central venous catheter. In an aspect, a disclosed IV administration of a disclosed treatment regimen can occur once every four hours at the infusion rate of from about 50 mL/hr to about 250 mL/hr (e.g., about 50, 75, 100, 125, 150, 175, 200, 225, 250 mL/hr) depending on the subject's age and condition/tolerance. In an aspect, one or more anti-mutant KRAS antibodies or a pharmaceutical formulation thereof can be delivered via an ambulatory infusion pump and subclavian catheter.

[0315] In an aspect, local administration can comprise delivery to one or more of the subject's body systems having cancerous cells or tumorous growth. In an aspect, the subject's one or more body systems having cancerous cells or tumorous growth can comprise the subj ect' s cardiovascular system, the subject's digestive system, the subject's endocrine system, the subject lymphatic system, the subject's muscular system, the subject's nervous system, the subject's reproductive system, the subject's respiratory system, the subject's skeletal system, the subject's urinary system, the subject's integumentary system, or any combination thereof.

[0316] In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of a disclosed treatment regimen. In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of one or more disclosed anti -mutant KRAS antibodies or a pharmaceutical formulation thereof. In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof, a disclosed targeted therapy, a disclosed composition, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof to identify an effective dose and/or to identify an effective dose eliciting only mild adverse and/or side effects.

[0317] In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of a disclosed treatment regimen in a specific or disclosed subject. In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of one or more disclosed anti -mutant KRAS antibodies or a pharmaceutical formulation thereof in a specific or disclosed subject. In an aspect, a disclosed method of treating and/or preventing cancer can comprise titrating the dose of a disclosed composition, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof to identify an effective dose and/or to identify an effective dose eliciting only mild adverse and/or side effects for a specific or disclosed subject.

[0318] In an aspect, administering comprises administering to the subject the maximum tolerated dose of the one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof. In an aspect, administering comprises administering to the subj ect less than the maximum tolerated dose of the one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof.

[0319] In an aspect, IV administration of a disclosed treatment regimen can comprise an outpatient setting. In an aspect, one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof can be administering prior to, concurrent with, or after administering of a disclosed targeted therapy. In an aspect, the order of administering the one or more disclosed antimutant KRAS antibodies or a pharmaceutical formulation thereof and the administering of any other therapeutic agent and/or targeted therapy can change during a treatment regimen.

[0320] In an aspect, a disclosed method of treating and/or preventing cancer can further comprise obtaining a biological sample from the subject prior to administering a disclosed treatment regimen. In an aspect, a disclosed method of treating and/or preventing cancer can further comprise obtaining a biological sample from the subject after administering a disclosed treatment regimen. In an aspect, a disclosed method of treating and/or preventing cancer can further comprise subjecting the biological sample to a cell-free DNA (cfDNA) analysis. cfDNA analyses are known to the skilled person in the art. In an aspect, a disclosed cfDNA analysis can be repeated one or more times. In an aspect, a disclosed obtaining step can be repeated one or more times.

[0321] In an aspect of a disclosed method of treating and/or preventing cancer, a disclosed cfDNA analysis can comprise next generation sequencing. In an aspect, next generation sequencing (NGS) can comprise using one or more commercially available platforms. Commercially available NGS sequencing platforms can comprise, for example, Guardant360 CDx (Guardant Health, Inc.), FoundationOne CDx (FICDx) (Foundation Medicine, Inc.), or Tempus xT (Tempus). In an aspect, a disclosed method can identify and/or characterize a disclosed mutant KRAS.

[0322] In an aspect of a disclosed method of treating and/or preventing cancer, next generation sequencing can comprise sequencing one or more cancer related genes. In an aspect of a disclosed method of treating and/or preventing cancer, sequencing one or more cancer related genes can comprise identifying one or more genomic aberrations. In an aspect, one or more genomic aberrations can comprise somatic genomic aberrations. In an aspect, the disclosed one or more somatic genomic aberrations can comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, or any combination thereof.

[0323] In an aspect of a disclosed method, one or more genomic aberrations in the biological sample can be detected. In an aspect, a disclosed method can further comprise detecting one or more genomic aberrations in the biological sample. In an aspect, a disclosed method can further comprise identifying one or more genomic aberrations in a panel of genes. In an aspect, disclosed genomic aberrations can be identified in a panel of genes. In an aspect, a disclosed panel of genes can comprise at least one gene, at least two genes, 3 or more genes, 5 or more genes, 7 or more genes, or 10 or more genes. In an aspect, a disclosed panel of genes can comprise 2 or more genes, 3 or more genes, 4 or more genes, 5 or more genes, 6 or more genes, 7 or more genes, 8 or more genes, 9 or more genes, or 10 or more genes. In an aspect, a disclosed panel of genes can comprise any combination of disclosed genes or disclosed cancer-related genes.

[0324] In an aspect, a disclosed method can comprise detecting the expression of one or more disclosed genes and/or one or more disclosed gene aberrations.

[0325] In an aspect of a disclosed method, the level of expression of one or more genomic aberrations can be tied to the aggressiveness and/or likelihood of survival. In an aspect of a disclosed method, the expression of the one or more genomic aberrations in a biological sample can be associated with the pathophysiological status of the subject suffering from breast cancer. In an aspect of a disclosed method, the absence and/or the presence of one or more genomic aberrations can be tied to the aggressiveness and/or likelihood of survival. In an aspect of a disclosed method, the absence and/or the presence of one or more genomic aberrations in a biological sample can be associated with the pathophysiological status of the subject suffering from breast cancer. In an aspect, a disclosed method can further comprise generating a library and/or database comprising a listing of genes and/or genomic aberrations affected by the administration of one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof only. In an aspect, a disclosed method can further comprise generating a library and/or database comprising a listing of genes and/or genomic aberrations affected by the administration of one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof and one or more targeted therapies.

[0326] In an aspect of a disclosed method of treating and/or preventing cancer, a disclosed cfDNA analysis can comprises quantification of one or more cancer related genes. In an aspect, if the expression and/or amount and/or presence of the disclosed one or more genomic aberrations in the pre-treatment biological sample is higher than the expression and/or amount and/or presence of the same one or more genomic aberrations in a control sample, then a disclosed method of treating and/or preventing cancer can comprise diagnosing the subject as being in need of precision cancer treatment. In an aspect, a disclosed control sample can be a sample obtained from a subj ect not having cancer. In an aspect, a disclosed control sample can be a pooled sample obtained from more than one subject not having cancer.

[0327] In an aspect, a disclosed method can comprise generating a control sample and/or a pooled control sample. In an aspect, a disclosed method can comprise generating a reference sample and/or a pooled reference sample. In an aspect, a disclosed method can comprise generating a range of control samples and/or pooled control samples. In an aspect, a disclosed method can comprise generating a range of reference samples and/or pooled reference samples.

[0328] In an aspect, if the expression and/or amount and/or presence of the disclosed one or more genomic aberrations in the post-treatment biological sample is lower than the expression and/or amount and/or presence of the same one or more genomic aberrations in a pre-treatment sample, then a disclosed method of treating and/or preventing cancer can comprise continuing to administer to the subject a disclosed treatment regimen. In an aspect, if the expression and/or amount and/or presence of the disclosed one or more genomic aberrations in the post-treatment biological sample is lower than the expression and/or amount and/or presence of the same one or more genomic aberrations in a prior post-treatment sample, then a disclosed method of treating and/or preventing cancer of treating and/or preventing cancer can comprise continuing to administer to the subject a disclosed treatment regimen.

[0329] In an aspect, a disclosed method of treating and/or preventing cancer can further comprise measuring the subject's tumor response to the precision cancer treatment. In an aspect, a subject's tumor response can comprise a partial response or a complete response. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one or more tumors by 25% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one or more tumors by 50% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one more tumors by about 100% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment.

[0330] In an aspect, a complete response can be defined as complete disappearance of all tumors with no recurrence of tumors for at least four weeks. In an aspect, a partial response can be defined as a 50% reduction in total tumor size with such reduction lasting at least four weeks. In an aspect, stable disease can be defined as less than 50% reduction in size but no more than 25% increase in size of the tumor mass lasting for at least twelve weeks.

[0331] In an aspect, a disclosed method of treating and/or preventing cancer can further comprise measuring the subject's molecular response to a disclosed treatment regimen. In an aspect, a disclosed molecular response can comprise a decrease in the number of somatic genomic aberrations in a disclosed biological sample obtained from the subject. In an aspect, disclosed somatic genomic aberrations can comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, fusions, or any combination thereof.

[0332] In an aspect, a disclosed molecular marker that can determine one or more suitable precision cancer treatments in one or more disclosed methods can be measured from a sample by high-density expression array, DNA microarray, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), real-time quantitative reverse transcription PCR (qRT-PCR), serial analysis of gene expression (SAGE), spotted cDNA arrays, GeneChip, spotted oligo arrays, bead arrays, RNA Seq, tiling array, northern blotting, hybridization microarray, in situ hybridization, whole-exome sequencing, whole-genome sequencing, liquid biopsy, next-generation sequencing, or any combination thereof.

[0333] In an aspect, a disclosed molecular marker can determine one or more suitable precision cancer treatments for use in a disclosed method of treating and/or preventing cancer can determined from the nucleic acid sequence of the at least one of circulating DNA and/or RNA. In an aspect, a disclosed molecular marker can be assessed from circulating tumor DNA and/or RNA (ctDNA and/or ctRNA); circulating cell-free DNA and/or RNA (cfDNA, cfRNA); or any combination thereof. ctDNA/ctRNA refers to tumor-derived fragmented DNA in the bloodstream that is not associated with cells. cfDNA/cfRNA refers to DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. In an aspect, cfDNA/ctDNA can include any whole or fragmented genomic DNA, or mitochondrial DNA, and/or cfRNA/ctRNA can include mRNA, tRNA, microRNA, small interfering RNA, long non-coding RNA (1 ncRNA). In an aspect, cfDNA and/or ctDNA can be a fragmented DNA with a length of at least about 50 base pair (bp), about 100 bp, about 200 bp, about 500 bp, or about 1 kbp. In an aspect, cfRNA and/or ctRNA can be a full length or a fragment of mRNA (e.g., at least 70% of full-length, at least 50% of full length, at least 30% of full length, etc.). In an aspect, a disclosed molecular marker can be directed against any cancer-related gene disclosed herein.

[0334] In an aspect, a disclosed method can further comprise surgically resecting the tumor from the subject. In an aspect, a disclosed method can further comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy.

[0335] For example, in an aspect, repeating one or more disclosed steps of a disclosed method can comprise repeating the administering to the subject the treatment regimen, one or more disclosed anti -mutant KRAS antibodies or a pharmaceutical formulation thereof, the targeted therapy, or any combination thereof, repeating the measuring of the subject's tumor response, repeating the obtaining of a biological sample from the subject, repeating the subjecting the biological sample to cfDNA analysis, repeating the administering of one or more additional therapeutic agents, or any combination thereof.

[0336] In an aspect, a disclosed molecular marker can be detected, quantified, and/or analyzed over time (at different time points) to determine the effectiveness of a disclosed treatment regimen (e.g., one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof) to the subject and/or to determine the response of a subject or subject's tumor to the precision cancer treatment (e.g., developing resistance, susceptibility, etc.). In an aspect, a disclosed method can comprise obtaining multiple measurements overtime from the same subject and same sample may be quantified at a single time point or over time. In an aspect, a disclosed treatment regimen treatment (e.g., a disclosed treatment regimen comprising one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof) can be designed and/or determined based on the cancer status and/or the changes/types of one or more molecular markers. In an aspect, the likelihood of success of a disclosed treatment regimen can be determined based on the cancer status and the type/quantity of one or more molecular markers.

[0337] In an aspect, a disclosed molecular marker can be derived from a gene expressed in one or more cells of a tumor or in an immune cell and can indicate immune suppressive tumor microenvironment, the development of cancer sternness, the onset of metastasis, cancer status, or any combination thereof. In an aspect, a disclosed molecular marker can be the protein or peptide encoded by the gene from which the molecular marker is derived and can be targeted by an antagonist or any other type of binding molecule to inhibit the function of the peptide.

[0338] Thus, in an aspect, increased expression (e.g., above a predetermined threshold) of a disclosed molecular marker derived from a disclosed gene related to immune suppressive tumor microenvironment can implicate the presence of immune suppressive tumor microenvironment, and can also implicate that an antagonist to the peptide encoded by the gene related to immune suppressive tumor microenvironment can have a high likelihood of success to inhibit the progress of the cancer by inhibiting immune suppressive tumor microenvironment and further promoting immune cell activity against tumor cells in such microenvironment. In an aspect, once the molecular marker has been identified, any suitable antagonist to a target gene or protein product can be used. For example, in an aspect, a specific kinase can be targeted by a kinase inhibitor, or a specific signaling receptor can be targeted by synthetic ligand, or a specific checkpoint receptor targeted by synthetic antagonist or antibody, etc. In an aspect, a disclosed antagonists to a target molecule herein can be administered before, after, or in combination with one or more disclosed anti-mutant KRAS antibodies or a pharmaceutical formulation thereof.

[0339] In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and/or can be of any race. In an aspect, a subject can have a terminal cancer. In an aspect, a disclosed subject can have any cancer characterized by and/or driving by a mutant KRAS. In an aspect, a disclosed subject can a combination of cancers including one or more characterized by and/or driving by a mutant KRAS. [0340] In an aspect, a disclosed targeted therapy can comprise one or more monoclonal antibodies. In an aspect, a disclosed monoclonal antibody can comprise an angiogenesis inhibitor (e.g., bevacizumab), a HER-2 targeted agent (e.g., trastuzumab, pertuzumab, etc.), an anti-CD20 monoclonal antibody (e.g., rituximab, obinutuzumab, etc.), or any combination thereof. In an aspect, a disclosed targeted therapy can comprise one or more small molecule inhibitors. In an aspect, a disclosed small molecule inhibitor can comprise a tyrosine kinase inhibitor (e.g., erlotinib, sunitinib, imatinib, dasatinib, etc.), a mTOR inhibitor (e.g., everolimus), a PARP inhibitor (e.g., olaparib), a CDK inhibitor (e.g., palbociclib, riboci clib, abermaciclib, etc.), a CD4 and/or CD6 inhibitor, or any combination thereof.

[0341] In an aspect, a disclosed targeted therapy can comprise abagovomab, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atinumab, atlizumab (tocilizumab), atorolimumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, blinatumomab, blosozumab, bococizumab, brentuxim abvedotin, briakinumab, brodalumab, brolucizumab, brontictuzumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, certolizumab pegol, cetuximab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, crenezumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, derlotuximab biotin, detumomab, dinutuximab, diridavumab, dorlimomab aritox, drozitumab, duligotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emibetuzumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, figitumumab, firivumab, flanvotumab, fletikumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab ozogamicin, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, idarucizumab, igovomab, imalumab, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin, infliximab, inolimomab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirvetuximab soravtansine, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-cd3, nacolomab tafenatox, namilumab, naptumomab estafenatox, namatumab, natalizumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placulumab, polatuzumab vedotin, ponezumab, priliximab, pritoxaximab, pritumumab, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranibizumab, raxibacumab, refanezumab, regavirumab, reslizumab, rilotumumab, rinucumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tarextumab, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, ticilimumab, tigatuzumab, tildrakizumab, tocilizumab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, vandortuzumab vedotin, vantictumab, vanucizumab, vapaliximab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab, zolimomab aritox, or any combination thereof.

[0342] In an aspect, a disclosed targeted therapy can comprise abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, alemtuzumab, alpelisib, atezolizumab, avelumab, axitinib, bevacizumab, binimetinib, blinatumomab, bosutinib, brentuximab, brigatinib, cabozantinib, carfilzomib, cemiplimab, ceritinib, cetuximab, gilteritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, daratumumab, dasatinib, denosumab, dinutuximab, durvalumab, duvelisib, elotuzumab, encorafenib, entrectinib, erdafitinib, erlotinib, fam-trastuzumab deruxtecan-nxki, gefitinib, gemtuzumab, ibritumomab tiuxetan, ibrutinib, imatinib, inotuzumab, ipilumumab, ivosidenib, lapatinib, larotrectinib, Lenvatinib, lorlatinib, margetuximab-cmkb, necitumumab, neratinib, nilotinib, niraparib, nivolumab, obinutuzumab, ofatumumab, olaparib, olaratumab, osimertinib, palbociclib, panitumumab, pazopanib, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, ribociclib, rituximab, rucaparib, sorafenib, sunitinib, talazoparib, tivozanib, tositumomab, trametinib, trastuzumab, tucatinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0343] In an aspect, a disclosed targeted therapy for oral administration can comprise abemaciclib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bosutinib, brigatinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, encorafenib, entrectinib, erdafitinib, erlotinib, gefitinib, gilteritinib, ibrutinib, imatinib mesylate, ivosidenib, lapatinib, larotrectinib, lorlatinib, lenvatinb, neratinib, nilotinib, niraparib, olaparib, osimertinib palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib malate, talazoparib, tivozanib, trametinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0344] In an aspect, a disclosed targeted therapy for intravenous administration can comprise ado- trastuzumab emtansine, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab vedotin, carfilzomib, cetuximab, cemiplimab-rwlc, certinib, copanlisib, daratumumab, dinutuximab, durvalumab, elotuzumab, fam-trastuzumab deruxtecan-nxki, gemtuzumab ozogamicin, ibritumomab tiuxetan, inotuzumab ozogamicin, ipilimumab, margetuximab-cmkb, necitumumab, nivolumab, obinutuzumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab and iodine 1131 tositumomab, trastuzumab, ublituximab-xiiy, or any combination thereof.

[0345] In an aspect, a disclosed targeted therapy for subcutaneous administration can comprise denosumab, ofatumumab, or any combination thereof.

[0346] In an aspect, a disclosed method of treating and/or preventing cancer can comprise administering to the subj ect a therapeutically effective amount of a targeted immunotherapy agent (e.g., fam-trastuzumab-deruxtecan-nxki; trastuzumab; Herceptin Hylecta (injectable Herceptin); Herceptin biosimilars (e.g., Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera); ado- trastuzumab emtansine; margetuximab-cmkb; pertuzumab, trastuzumab, and hyaluronidase-zzxf; pertuzumab; sacituzumab govitecan-hziy; or any combination thereof).

[0347] In an aspect, a disclosed method can be modified or one or more steps of a disclsoed method can be modified. In an aspect, a disclosed method of treating and/or preventing cancer and/or metastatic cancer can comprise modifying or changing one or more features or aspects of one or more steps. In an aspect, a method can be altered by changing the amount of a disclosed treatment regimen, a disclosed anti-mutant KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agent, or a combination thereof administered to a subject, or by changing the frequency of administration of disclosed treatment regimen, a disclosed anti-mutant KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agents, or a combination thereof to a subject, by changing the duration of time that disclosed treatment regimen, a disclosed anti-mutant KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti -cancer agent, a disclosed chemotherapeutic agent, or a combination thereof is administered to a subject, or by substituting for one or more of the disclosed components and/or reagents with a similar or equivalent component and/or reagent. The same applies to all disclosed treatment regimens, disclosed antimutant KRAS antibodies, disclosed targeted therapies, disclosed pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed chemotherapeutic agents, or combinations thereof.

[0348] In an aspect, a disclosed method can improve and/or extend the survivability of the subject, can improve a subject's quality of life, can increase and/or prolong a subject's life span, or any combination thereof. In an aspect, the subject's life expectancy can be compared to the life expectancy of a control (i.e., no treatment with a disclosed anti-mutant KRAS antibody). In an aspect, a control can be a subject not receiving a disclosed pharmaceutical composition. In an aspect, a control can be a pooled number of subjects not receiving a disclosed pharmaceutical composition. In an aspect, a control is one or more subjects having the same type of cancer condition as the subject. In an aspect, life expectancy can be defined as the time at which 50 percent of subjects are alive and 50 percent have passed away.

[0349] In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subject with the identical or near identical viral infection and the identical or near identical predicted outcome.

[0350] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subj ect. In an aspect, continuing to treat the subj ect can comprise continuing to administer a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof).

[0351] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administered to the subject, changing the frequency of a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administration, changing the duration of a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administration, changing the route of a a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., one or more disclosed anti -mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administered to the subject, changing the frequency of a disclosed composition (i.e., one or more disclosed antimutant KRAS antibodies and/or a pharmaceutical formulation thereof) administration, changing the duration of a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof) administration, changing the route of a disclosed composition (i.e., one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof), or any combination thereof.

[0352] In an aspect, a disclosed method can reduce the risk of developing one or more metastases. A reduction in the risk of developing one or more metastases comprises a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount in the risk of metastases when compared to a control subject (such as, for example, a subject that has not received one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof).

[0353] In an aspect, a disclosed method can comprise improving and/or enhancing the subject's quality of life and/or movement. In an aspect of a disclosed method, a disclosed improvement and/or enhancement (such as, for example, in the subject's quality of life and/or movement) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of improvement and/or enhancement when compared to a control subject (such as, for example, a subject that has not received one or more disclosed anti -mutant KRAS antibodies and/or a pharmaceutical formulation thereof). In an aspect, a disclosed improvement and/or enhancement (such as, for example, in the subject's quality of life and/or movement) can comprise a 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% or any amount of an improvement and/or enhancement when compared to a control subject (such as a subject that has not received one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof). [0354] In an aspect, a disclosed diminishment (such as, for example, the size of one or more tumors) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of a decrease when compared to a control subject (such as, for example, a subject that has not received one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof). In an aspect, a disclosed diminishment (such as, for example, the size of one or more tumors) can comprise a 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% or any amount of a decrease when compared to a control subject (such as a subject that has not received one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof).

[0355] In an aspect, a disclosed method can further comprise monitoring the subject following the administering step and/or the treating step to generate a compilation of biochemical and/or physiological and/or behavioral data. In an aspect, a disclosed compilation of data can be used to identify a trend or a pattern. In an aspect, a disclosed compilation of data can be used to guide and/or inform a skilled clinician in a decision-making process regarding treatment and/or testing. In an aspect, for example, a clinical can decide to change an aspect of the subject's treatment and/or change the subject's diagnosis or prognosis.

[0356] In an aspect of a disclosed method, administering one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof can be daily, weekly, bi-weekly, monthly, or yearly. In an aspect, one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof can be administered to a subject one or times per day (e.g., lx per day, 2x per day, 3x per day, more than 3x per day, etc.), one or times per week, one or more times per month, or one or more times per year.

[0357] In an aspect, a disclosed method can further comprise monitoring the subject's metabolic and/or physiologic improvement following the administering and/or treating step and/or following the administering and/or treating steps. In an aspect, a clinician can measure and/or determine the subject's metabolic and/or physiologic status over time to identify one or more improvements and/or one or more diminishments. In an aspect of a disclosed method, a clinician can use the subject's metabolic and/or physiologic status and/or the trend of the subject's metabolic and/or physiological status and/or trend to make a treatment decision and/or to modify an aspect of a disclosed method and/or to continue treating the subject and/or continue to administer one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof. In an aspect, metabolic and/or physiologic data can inform the clinician when make subsequent treatment decisions. [0358] In an aspect, a disclosed method can further comprise repeating one or more disclosed steps of a disclosed method. In an aspect, a disclosed method can further comprise continuing to administer to the subject a therapeutically effective amount of one or more disclosed anti-cancer therapies.

[0359] In an aspect, a disclosed method can further comprise generating and/or making one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof. In an aspect, a disclosed method can further comprise validating and/or characterizing one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof. For example, in an aspect, validating and/or characterizing one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof can comprise measuring, ascertaining, and/ or determining the purity and/or efficacy of the one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof.

E. Kits

[0360] Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies. Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies. Disclosed herein is a kit comprising on Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS, wherein the one or more disclosed antimutant KRAS antibodies are used to treat a subject having one or more cancers. Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-mutant KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers.

[0361] Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies, wherein the pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS are used to treat a subj ect having one or more cancers. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies, wherein the pharmaceutical formulation comprising one or more disclosed anti -mutant KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers.

[0362] Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti- mutant KRAS antibodies, wherein the one or more disclosed anti-mutant KRAS antibodies are used to treat a subject having one or more cancers for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies, wherein the one or more disclosed anti-mutant KRAS antibodies are used to treat a subj ect having cancer or metastatic cancer for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies, wherein the pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies are used to treat a subject having one or more cancers for one or more treatment cycles.

[0363] Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-mutant KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-mutant KRAS antibodies and the targeted therapies are used to treat a subj ect having cancer or metastatic cancer for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies and one or more targeted therapies for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-mutant KRAS antibodies one or more targeted therapies, wherein the pharmaceutical formulation comprising one or more disclosed anti -mutant KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers for one or more treatment cycles.

[0364] In an aspect, by using a disclosed kit, (i) the risk of developing metastases can be prevented and/or decreased; (ii) the survival of the subject can be prolonged; (iii) the subject's quality of life can be enhanced and/or improved; (iv) the likelihood of surgical intervention can be reduced and/or minimized; (v) preventing and/or delaying recurrence of the cancer; (vi) the size of one or more tumors in the subj ect can be reduced and/or decreased; (vii) one or more tumors in the subj ect can be eliminated; (viii) extending and/or prolonging disease-free or tumor-free survival time; (ix) increasing and/or lengthening overall survival time; (x) reducing and/or minimizing the frequency of treatment; (xi) relieving and/or ameliorating one or more symptoms of the cancer; (xii) reducing and/or decreasing tumor burden, (ix) preventing and/or facilitating surgical intervention; (xiii) normal metabolism of one or more organ systems in the subject can be improved and/or restored, (xiv) one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation can be restored and/or improved, or (xv) any combination thereof.

[0365] In an aspect, a disclosed kit can comprise one or more additional and/or therapeutic agents. "Agents" and "Therapeutic Agents" are known to the art and are described herein. In an aspect, a disclosed agent or a disclosed therapeutic agent can comprise one or more monoclonal antibodies, one or more antibody-drug conjugates, one or more kinase inhibitors, one or more CDK4 and/or CDK6 inhibitors, one or more mTOR inhibitors, one or more ADK inhibitors, one or more PI3K inhibitors, one or more PARP inhibitors, or any combination thereof.

[0366] In an aspect, a disclosed kit can comprise a disclosed chemotherapeutic agent. In an aspect, a disclosed chemotherapeutic agent can comprise anthracycline-based chemotherapy or can comprise non-anthracycline-based chemotherapy. In an aspect, a disclosed chemotherapeutic agent can comprise oxaliplatin, doxorubicin, daunorubicin, docetaxel, mitoxanthrone, paclitaxel, digitoxin, digoxin, septacidin, 5 -fluorouracil and epirubicin, doxorubicin and cyclophosphamide, epirubicin and cyclophosphamide, docetaxel and carboplatin, or any combination thereof. In an aspect, a disclosed chemotherapeutic agent can be formulated as a polymeric micelle formulation, a liposomal formulation, a dendrimer formulation, a polymer-based nanoparticle formulation, a silica-based nanoparticle formulation, a nanoscale coordination polymer formulation, an inorganic nanoparticle formulation, or any combination thereof.

[0367] In an aspect, a disclosed kit can comprise targeted immunotherapy agent (e.g., fam- trastuzumab-deruxtecan-nxki; trastuzumab; Herceptin Hylecta (injectable Herceptin); Herceptin biosimilars (e.g., Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera); ado-trastuzumab emtansine; margetuximab-cmkb; pertuzumab, trastuzumab, and hyaluronidase- zzxf; pertuzumab; sacituzumab govitecan-hziy; or any combination thereof).

[0368] In an aspect, a disclosed kit can be used to validate and/or characterize (i) one or more disclosed anti-mutant KRAS antibodies having an IgG backbone and/or a pharmaceutical formulation thereof, and/or (ii) one or more disclosed anti-mutant KRAS antibodies having a dlgA and/or a pharmaceutical formulation thereof. In an aspect, validating and/or characterizing can comprise measuring, ascertaining, and/ or determining the purity and/or efficacy of the one or more disclosed anti-mutant KRAS antibodies and/or a pharmaceutical formulation thereof.

[0369] In an aspect, a disclosed kit can comprise one or more disclosed anti-KRAS antibodies formulated as a capsule and/or tablets for oral administration. In an aspect, a disclosed kit can comprise one or more disclosed anti-KRAS antibodies formulated as a solution for intravenous administration. [0370] In an aspect, a disclosed kit can comprise one or more targeted therapies. In an aspect, a disclosed targeted therapy can be a commercially available targeted therapy. In an aspect, a disclosed targeted therapy can be an experimental targeted therapy. Targeted therapies are discussed supra.

[0371] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, treating a subject diagnosed with or suspected of having a disease or disorder such as cancer). Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0372] In an aspect, a disclosed kit for use in a disclosed method can comprise one or more containers holding a disclosed treatment regimen, a disclosed anti-mutant KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agent, or a combination thereof, and a label or package insert with instructions for use. In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold one or more disclosed anti-mutant KRAS antibodies, one or more disclosed pharmaceutical formulations comprising one or more disclosed anti-mutant KRAS antibodies, or any combination thereof, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert can indicate one or more disclosed anti-mutant KRAS antibodies, disclosed pharmaceutical formulations, or any combination thereof can be used for treating, preventing, inhibiting, and/or ameliorating a disease or disorder or complications and/or symptoms associated with cancer or metastatic cancer (e.g., cancer or breast cancer). A kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes.

F. Miscellaneous

[0373] Disclosed herein is an anti-mutant IDH1 antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains. Disclosed herein is an anti-mutant IDH1 antibody comprising an IgG backbone comprising (i) a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and (ii) a variable heavy chain region (VH) comprising 3 CDRs and a constant heavy chain region, wherein the VH is linked to the constant heavy chain region, and wherein the constant heavy chain region is linked to the PIGR biding domain. In an aspect, a disclsoed antibody can recognize the mutant form of IDH1. In an aspect of an anti-mutant IDH1 antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:93, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:91 or SEQ ID NO:92. In an aspect a disclosed VH can be connected to a constant heavy chain region, GS-based spacer, and PIGR peptide binding domain. In an aspect, a disclosed anti-mutant IDH1 having an IgG backbone antibody is specific for IDH1 (mutant ^R132H). in an aspect, a disclosed GS-based spacer can comprise the sequence set forth in SEQ ID NO:95. In an aspect, a disclosed PIGR peptide binding domain can comprise the sequence set forth in SEQ ID NO:09.

[0374] Disclosed herein is an anti-mutant IDH1 antibody comprising a dimeric IgA backbone. Disclosed herein is anti-mutant IDH1 antibody comprising a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs; wherein the VH is linked to a constant heavy chain region; wherein the two monomers are linked together. In an aspect, a disclosed antibody can recognize the mutant form of IDH1. In an aspect of an antimutant IDH1 antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO: 93, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:91 or SEQ ID NO:92. In an aspect, two monomers are linked together by the sequence set forth in SEQ ID NOVO, SEQ ID NO:94, SEQ ID NO: 112, or SEQ ID NO: 113. In an aspect, a disclosed anti-mutant IDH1 having a dimeric IgA backbone antibody is specific for IDH1 (mutant ^R132H).

[0375] Isocitrate dehydrogenases such as IDH1 catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes indicates roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-di enoyl - CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. This product is specific for IDH1 (mutant ^R132H). [0376] In an aspect, a truncated version of the VH of SEQ ID NO:01 can comprise the sequence set forth in SEQ ID NO: 127. In an aspect, a truncated version can comprise no spacer between the Fc domain and the PIGR peptide binding domain. In an aspect, a truncated version of the VH of SEQ ID NO:01 can comprise 9 fewer amino acids on the N-terminus of the Fc domain. In an aspect, an anti-mutant KRAS IgG antibody having a VH, constant heavy chain region, GS-based spacer, and PIGR peptide binding domain comprising the sequence set forth in SEQ ID NO: 127 can be less effective than other anti-mutant KRAS antibodies comprising another disclosed VH.

VIII. EXAMPLES

[0377] The Examples that follow are illustrative of specific aspects of the invention, and various uses thereof. The Examples set forth for explanatory purposes only and are not to be taken as limiting the invention.

Materials and Methods

[0378] Human Samples. A lung cancer tissue microarray of total 30 cases including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma and bronchioloalveolar carcinoma with matched metastatic carcinoma and cancer adjacent tissue, with available pathology grade and survival data was procured from US Biomax.

[0379] Cell Lines. OVCAR3 (RRID:CVCL_0465), A427 (RRID:CVCL_1055), SK-LU-1 (RRID:CVCL_0629), HEK293T (RRID:CVCL_0063), NCI-H23 (RRID:CVCL_1547), NCI- H647 (RRID:CVCL_1574) cell lines were purchased from ATCC (Manassas, VA). IDH1^+/+ and IDH1^R132H/+ HCT116 (RRID:CVCL_0291) cell lines were purchased from Horizon discovery. E/G7 - ablated OVCAR3 cells was generated in the lab (Hong, D.S., et al. (2020) N Engl J Med. 383: 1207-1217). Brpkpl lO was established in the lab (Allegrezza, M.J., et al. (2016) Cancer Res 76:6253-6265) and KPMSH2^KIN is a new model of lung cancer developed also in the laboratories of the present Inventors that carries the same epitope recognized in human G12D-mutated KRAS. Cell lines were routinely cultured in R10 (RPMI-1640, 10% FBS, penicillin (100 lU/mL), streptomycin (100 pg/mL), L-glutamine (2 mM), sodium pyruvate (0.5 mM)) media (Thermo). HEK293T cell line was routinely cultured in D10 (DMEM, 10% FBS, penicillin (100 lU/mL), streptomycin (100 pg/mL), L-glutamine (2 mM), sodium pyruvate (0.5 mM) media (Thermo). Cell lines were routinely tested for negative mycoplasma contamination.

[0380] Animal Models. For mouse models, three different strains were used. Female, 4-6 weeks old -deficient (Ragl’¹’) mice (RRID:IMSR_J AX: 003729) and female, 7 weeks old C57BL/6J mice (RRID:IMSR_JAX:000664) were purchased from The Jackson Laboratory. NOD.Cg- Prkdc^scld Il2rg ^mlWjlI zS (NSG) mice (RRID:IMSR_JAX:005557), originally procured from The Jackson Laboratory, were maintained by the Moffitt Cancer Center animal facility. All animals were maintained by the animal facility of the Moffitt Cancer Center and Duke School of Medicine, housed in cages of up to 5 mice per cage, in a temperature controlled (18-23°C), 40-60% humidity, 12 h light/dark cycle facility. Animal studies were performed in accordance with Institutional Animal Care and Use Committee at the University of South Florida Research Integrity and Compliance department (IACUC protocols#IS00006655 and #IS00009457) and at the Duke University and Division of Laboratory Animal Resources (IACUC protocol# A011-23-01).

[0381] Constructs and Transduction. Human E/G7 -coding sequence was cloned into pLVX- IRES-ZsGreenl lentiviral vector (Genscript) (Wang, X., etal. (2022). J Med Chem 65:3123-3133). Constructs encoding Wild-type or G12D mutated KRAS fused with PAmCherryl (pLenti- TO/CMV-PAmCherryl-KRAS, G12D or WT) (Brahmer, J.R., etal. (2010) J Clin Oncol 28:3167 - 3175) were procured from Dr. Xiaolin Nan Lab, Oregon Health & Science University. The sequence integrity and accuracy of all constructs was assessed and confirmed by sequencing services from GeneWiz.

[0382] Virus Production and Transduction. Lentiviral particles were generated by co-transfecting HEK 293T/17 (ATCC) with pLVX-IRES-PIGR-ZsGreen, or pLenti-TO/CMV-PAmCherryl- KRAS (G12D mutated KRAS or WT) and packaging/envelope vector pMD2.G (RRID:Addgene_12259) and psPAX2 (RRID:Addgene_12260) using Lipofectamine-3000 (Invitrogen) and the viral supernatant was harvested 48 h after 5/ I 0⁵ HCT116 or OVCAR3 cells were seeded in a 6-well plate with 3 mL of the corresponding 0.45 pL filtered viral supernatant with added 10 pg/mL polybrene (Millipore). The plates were spun for 90 min at 32 °C and 1200 g. 12 h after transduction the medium was changed to R10 and 48 h later the expression of the target gene was verified under microscope for KRAS transductions and selected by FACS-sorted for ZsGreen expression (PIGR).

[0383] Tumor Models. Flank tumors were initiated by injecting l * 10⁷ KRAS^{WT or} KRAS^G12D transduced OVCAR3 or A427; or 5* 10⁶ IDH1^{WT or Mut} HCT116 cells or 5* 10⁵ Brpkpl 10 cells; or 1 * 10⁶ KPMSH2^KIN cells in PBS. SK-LU-1 tumors were initiated by injecting 1 * 10⁷ cells in PBS admixed with 1 : 1 Matrigel into flanks.

[0384] Tumor volume was calculated as: 0.5 * (L * W²), where L is length and W is width. Intratumoral or peritumoral injections, as well as intraperitoneal injections of antibodies were done on multiple times at 3-4 days interval starting from day 7 for OVACR3, A427, HCT116, Brpkpl 10 and KPMSH2^KIN tumors or from day 20 for SK-LU-1 tumors after the tumor challenge at a dose of 100 pg / 20 g. MRTX1133 (MedChemExpress, #HY-134813) was injected daily or multiple times at 3-4 days interval starting from day 7 for OVACR3 and A427 or from day 20 for SK-LU- 1 tumors at a dose of 200 pg / 20 g. CD8 T cell depletion has been performed using aCD8 antibodies (BioXCell), injected at same frequency of injected antibodies, at a dose of 200 pg / 20 g-

[0385] Recombinant Antibody Production. Anti -KRAS ^G12D, and anti-IDHl^R132H antibody variable heavy (VH) and variable light (VL) sequences were obtained from the patent US10844136B2 and CN106957367A, respectively. VH sequences followed by human IgAl or IgG4 heavy chain constant region sequences in frame were cloned into PBMN-I-GFP vector (RRID:Addgene_1736). VL sequences along with human kappa light chain constant region sequences in frame were cloned into pVITROl (Genscript). Vectors, coding for all the VH and VL, were produced by Genscript. J-chain encoding pcDNA3.0 vector was procured from Addgene (RRID: Addgene_145146).

[0386] For recombinant dimeric and monomeric KRAS^G12D-IgAl and KRAS^G12D-IgG4 antibody production, HEK293T cells were retrovirally transduced with antibody heavy chain encoding PBMN-I-GFP vector and sorted for viable GFP⁺ cells, followed by transfection with antibody light chain encoding p Vitro 1 vector and selected using Hygromycin, and finally those cells were transfected with J-chain encoding pcDNA3.0 vector and selected using G418. Heavy chain plus light chain plus J-chain expressing HEK293T cells were grown in suspension for 5-7 days in Freestyle 293 expression media (Thermo) for dimeric KRAS^G12D-IgA antibody production. Similarly, for monomeric KRAS^G12D-IgAl or KRAS^G12D-IgG4, HEK293T cells expressing only light chain and respective heavy chain were used. Supernatants were concentrated through a 100 kDa membrane and antibodies were purified using IgA or IgG purification columns (Ligatrap). All transfections were performed using Lipofectamine 3000 (Thermo). Cell lines were routinely tested for negative mycoplasma contamination. Dimeric and monomeric IDHl^R132H-IgAl, and monomeric IDHl^R132H-IgG4 antibodies and some additional quantity KRAS^G12D-IgG4 antibodies were procured from GenScript.

[0387] Fluorescence-activated Cell Sorting (FACS). Sorting of antibody heavy chain-transduced HEK293T cells (GFP expressing) were performed by staining with DAPI (Thermo Scientific) viability dye and gated for DAPTGFP⁺ cells. Similarly, PIGR-transduced HCT116 cells were sorted by gating DAPTGFP⁺ cells. Samples were subsequently fluorescence-activated cell sorting (FACS) sorted using BD FACS ARIA.

[0388] One hundred thousand KRAS^G12D transduced OVCAR3 cells were placed in 6-well plates. After 12 h wells were washed, and fresh medium was added, and cells were treated with antihuman KRAS^G12D-IgAl or KRAS^G12D-IgG4 or non-specific human IgA (Abeam, ab91025) at 0.5 pg/mL final concentration or vehicle (PBS) and incubated for 16 h in a 37 °C incubator. Total apoptotic cells (annexin V⁺ propidium iodide ) were analyzed by flow cytometry. [0389] MTT Assay. Five thousand OVCAR3 wild-type or G12D mutated KRAS-transduced or untraduced) or SK-LU-1 cells, or five hundred HEK293T cells were seeded in each well of 96- well plates. After 12 h cells were washed with PBS, and fresh medium was added, and were treated with anti-human KRAS^G12D-IgAl or non-specific human IgA (Abeam, ab91025) at 0.5 pg/mL final concentration or vehicle (PBS) and the medium was changed after 16 h incubation in a 37 °C incubator to remove the treatment. Proliferation was measure at 3, 5, or 7 days. MTT reagent solution (10 pL of 5 mg/mL) was added to the media of cultured cells and incubated for 3 hr. The precipitates were dissolved in DMSO, after remove the medium, and absorbance were measured at 570nm. Fold changes were calculated by dividing with the mean absorbance of the replicates of respective vehicle-treated cell lines.

[0390] Immunofluorescence and Confocal Microscopy. Anti-human KRAS^G12D-IgAl or KRAS^G12D-IgG4 antibodies were conjugated with Al exaFluor 488-conjugation kit (Thermo). Fifty thousand OVCAR3 (transduced with wild-type or G12D mutated KRAS, fused with PAmCherry) cells were placed onto a coverslip within 6-well plates and after 12 h treated with the conjugated antibodies for different temporal points. PAmCherry was photoactivated using the Leica TCS SP8 DAPI bandpass filter cube (Excitation BP 450 nm - 490 nm) using the widest aperture. Exposure time was dependent on the day of the experiment and varied between 20 to 30 seconds and was optimized using positive and negative controls. The same exposure time was used for all treatments. The gain for the Hoechst channel was adjusted to compensate for photobleaching due the exposure time required for photoactivating PAmCherry. Images were acquired with a 40X/1.3 NA objective in a confocal microscope (Leica SP8) using LAS X (v.3.5.5.19976) software. Hoechst, Alexa Fluor 488, PAmCherry were excited with laser lines 405 nm, 488 nm, 552 nm respectively. Emission was captured through band pass settings 415 nm - 480 nm, 500 nm - 525 nm, 592 nm - 651 nm, respectively. For the highest resolution images, the same parameters were used but the pixel resolution was increased to 2048 x 2048 and the images were taken with speed = 400 and z = 0.5 pm.

[0391] Exocytosis of KRAS^G12D and LC-MS/MS

[0392] Five hundred thousand OVCAR3 (transduced with wild-type or G12D mutated KRAS, fused with PAmCherry) cells were placed in 100 mm x 20 mm cell culture plates and treated with or without anti-human KRAS^G12D-IgAl or KRAS^G12D-IgG4 or non-specific human IgA (Abeam, ab91025) at 0.5 pg/mL final concentration or vehicle (PBS) in low serum media. After 12 h, conditioned medium was collected and filtered for contaminant debris removal. Proteins were extracted from the conditioned medium, reduced by DTT, digested by trypsin, and subjected to mass spectrometry analysis by the Moffitt Cancer Center Proteomics Facility. MaxQuant (version 1.5.2.8) was used to analyze the data, identify, and quantify the proteins (Biswas, S., et al. (2021) Nature 591 :464-470).

[0393] Western blot, Native Gel Electrophoresis, and Co-immunoprecipitation (Co-IP). Cells were lysed in RIPA buffer (Thermo) with protease-phosphatase inhibitor cocktail (CST, #5872S) and cleared by centrifugation. Proteins were quantified by BCA assay (Thermo). Membranes were blotted with recombinantly produced anti-KRAS^G12D-IgAl or anti-KRAS^G12D-IgG4 or anti- IDHl^R132H-IgAl or anti-IDHl^R132H-IgG4 antibodies; or commercial anti-mCherry Rockland, #600-401-P16, RRID:AB_2614470), anti-human immunoglobulin heavy alpha chain (Thermo Fisher Scientific, #A18781, RRID:AB_2535558), or anti-human immunoglobulin heavy gamma (plus light) chain (Thermo Fisher Scientific, #A18805, RRID:AB_2535582), or anti-human immunoglobulin kappa chain (R&D Systems, #MAB 10050), or anti-human J-chain (Thermo Fisher Scientific, Mcl9-9, #MA1-8O527, RRID:AB_934333), or anti-human Rab5A (Proteintech, #11947-1-AP, RRID:AB_2269388), or anti-human Rab7A (Proteintech, #55469-l-AP, RRID:AB_11182831), or anti-human Rab8A (Proteintech, #55296-l-AP, RRID:AB_10858398), or anti-human Rabi 1 A (Proteintech, #20229-l-AP, RRID:AB_10666202), or anti-human PIGR (Abeam, #ab96196, RRID:AB_10677612), or anti-human KRAS^G12D (CST, #14429, D8H7, RRID:AB_2728748) or anti-human P-actin (CST, #5125, 13E5, RRID:AB_1903890), antibodies. Lysates of A427 cells treated with KRAS^G12D-specific IgA or MRTX1133 for different time points were probed with antibodies against total ERK1/2 (CST, #9102, RRID:AB_330744) and phosphorylated ERK1/2 (CST, D13.14.4E, #9102, RRID:AB_330744). Blots were then probed with appropriate horse radish peroxidase (HRP)-conjugated secondary antibodies (room temperature for 1-2 hours), unless the primary antibodies are HRP-conjugated, and immunoreactive bands were developed using Enhanced Chemiluminescence (ECL) substrate (GE Healthcare).

[0394] For the native gel electrophoresis, 5 pg of dimeric KRAS^G12D-IgAl, dimeric IDH^R132H- IgAl, monomeric IDH^R132H-IgAl and irrlgA were diluted using Tris-Glycine Native Sample Buffer (ThermoFisher, #LC2673) and ran in a native gel, 12% Tris-Glycine Gel (Invitrogen, # XP00120BOX) for 1 hour at 220V. The gel was stained by overnight shaking with Invitrogen™ Colloidal Blue Staining Kit (Invitrogen, #LC6025). Then, the staining solution was replaced with deionized water, followed by overnight shaking until the gel had a clear background. The gel was scanned in a Canon TR4700 series HTTP.

[0395] For co-immunoprecipitation, cells were lysed using non-reducing non-denaturing lysis reagent provided in the co-immunoprecipitation (co-IP) kit (Pierce, Cat#26149) used. Proteins were immunoprecipitated using anti-human PIGR-secretory component (Abeam, SC-05, #ab3924, RRID: AB 2261963) or anti-human Rab5A, or anti-human Rab7A, or anti-human Rab8A, or antihuman Rabi 1 A, or anti-human IgA (Abeam, EPR5367-76, #abl24716, RRID:AB_10976507). Proteins from concentrated conditioned media from anti-human KRAS^G12D-IgAl or KRAS^G12D- IgG4 or non-specific human IgA or vehicle treated 0VCAR3 cells were immunoprecipitated using anti -human PIGR-secretory component. The elutes were ran for western blotting. For analyzing changes in intracellular KRAS^G12D protein level upon antibodies-treatment, lysates of KRAS^G12D- transduced 0VCAR3 or A427 cells, treated every 4 hours for a total of 12 hours, were used for western blotting.

[0396] Transwell and Transcytosis Assay for Expelling ofKRAS^G12D.

[0397] KRAS^G12D OVCAR3 cells (2* 10⁵) were seeded in the upper chamber of a transwell system (Coming® 3413 Transwell® 6.5 mm Polycarbonate, membrane Inserts Pre-Loaded in 24-Well Culture Plates, Pore Size: 0.4 pm) in 200 pL. In addition, 1 mL of fresh medium was added in the basal chamber. The cells were cultured in the incubator at 37 °C and 5% of CO2 during 3 days to create a monolayer. KRAS^G12D IgAl or KRAS^G12D IgG4 or non-specific human IgA antibodies were biotinylated using a Biotinylation Kit (Fast, TypeB)by following the manufacture's protocol. Then, 1 pg of respective biotinylated antibody was added to the upper chamber. After overnight incubation, the supernatant from the upper and basal chambers were collected into separate microcentrifuge tubes and subjected to streptavidin pull-down using Dynabeads MyOne streptavidin Tl. Briefly, 10 pL of beads per sample were washed according to the manufacture's recommendation, added to each sample and then incubated overnight at 4 °C with head-over rotation. The beads were collected my magnetic separation for 5 min and washed 3 times in PBS containing 0.1% BSA. Finally, the beads were resuspended in 100 pL of PBS and used for performing dot blots.

[0398] For dot blots, 10 pL of beads were blotted onto a nitrocellulose membrane and dried at room temperature 1-2 hours. Then, membranes were blocked using 5% BSA in TBS-T with a gentle agitation for 1 hour at room temperature. Appropriate primary antibodies (ahuman-IgA- HRP, ahuman-IgG-HRP and aKRAS^G12D) were added immediately and incubated 1 hour at room temperature with gentle rotation. After 3 washes, blots were directly chemiluminescent-developed when probed with HRP conjugated antibodies ahuman-IgA/IgG antibodies, or first incubated with a secondary antibody and developed.

[0399] Multiplex Immunohistochemistry

[0400] FFPE tissue microarray was immunostained using the PerkinElmer OPAL TM Automation H4C kit (Waltham, MA) on the BOND RX autostainer (Leica Biosystems, Vista, CA) and the following anti-human antibodies: IgA (Abeam, EPR5367-76, abl24716, RRID:AB_10976507; 1 : 1000), IgG (Abeam, EPR4421, abl09489, RRID:AB_10863040; 1 :500), plgR (Abeam, ab96196, RRID:AB_10677612; 1 : 100), CD3 (Thermo Fisher Scientific; Cat# MA5-14524, Clone SP7; RRID: AB_10982026, 1 : 100), and pan-cytokeratin (PCK, Dako, AE1/AE3, M3515, 1 :200). Nuclei were stained with DAPI. Precisely, tissues were baked at 65 °C for 2 hours then transferred to the BOND RX (Leica Biosystems) followed by automated deparaffinization, antigen retrieval using OPAL H4C procedure (PerkinElmer). Autofluorescence slides (negative control) were included, which use primary and secondary antibodies omitting the OPAL fluors. Slides were scanned and imaged with the PerkinElmer Vectra®3 Automated Quantitative Pathology Imaging System. Multi-layer TIFF images were exported from InForm (PerkinElmer) and loaded into HALO (Indica Labs, New Mexico) for quantitative image analysis. Each fluorescent fluorophore is assigned to a dye color and positivity thresholds were determined per marker based on published nuclear or cytoplasmic staining patterns. Tumor islets and stroma were distinguished by PCK staining.

[0401] The Cancer Genome Atlas (TCGA) Data Analysis. Molecular data for PIGR mRNA expression (RNA Seq V2 RSEM) from TCGA, Firehose Legacy for several human cancer types were analyzed and graphically exported from the eBio Cancer Genomics Portal (www.cbioportal.org/).

[0402] Statistical Analyses. Unless mentioned otherwise all data are presented as mean ± SEM. Two-tailed t-tests (unpaired and paired, as appropriate) were performed between two groups, and one-way ANOVA were performed for comparisons between more than two groups, unless indicated otherwise. A significance threshold 0.05 for P values was used. Analyses were carried out in Graph Pad Prism (v.9.0).

Rationale for Examples 1 - 5

[0403] It has been shown that the IgA/IgM polymeric immunoglobulin receptor (PIGR) is quasiuniversally expressed in human ovarian (Biswas, S., et al. (2021) Nature 591 :464-470; Harjes, U. (2021) Nat Rev Cancer 21 : 215) and endometrial cancer cells (Mandal, G., et al. (2022) Cancer Res 82:859-871; Osorio, J.C., et al. (2022) Cancer Res 82:766-768). This function allows transcytosis of dlgA through these tumor cells.

[0404] However, it was unclear whether IgA transcytosis also occurred in non-gynecologic tumors. Furthermore, IgA transcytoses through endosomes (Borrok, M.J., etal. (2018. JCI Insight 3), which could prevent direct contact with specific antigens inside tumor cells. Even if transcytosing IgA is not "shielded" by endosomes, targeted antigens could not co-localize inside tumor cells. Experimentation with these processes could determine if it is possible for engineered dlgA to target intracellular molecules, with important therapeutic implications: First, the mechanisms of resistance that invariably follow the administration of small molecule inhibitors (Gonzalez-Munoz, A., etal. (2012) MA bs 4:664-672) could be still sensitive to antibody-mediated neutralization, and vice versa. Second, the half-life of unmodified IgA ~ 6 days, but can be further optimized to increase stability (Sterlin, D., et al. (2021). 106:9-10). Third, dlgA is particularly abundant at mucosal surfaces, indicating that exogenous dlgA could be safely administered (Woof, J.M., et al. (2011) Mucosal Immunol 4:590-597). In Examples 1-5, the feasibility and therapeutic potential of targeting common mutated oncodrivers using recombinant dlgA was investigated. The results presented herein provide a rationale for developing dlgA-based therapeutics to neutralize various intracellular antigens in human cancer and other diseases.

Example 1 Mutation-Specific dlgA Neutralized Intracellular KRAS^G12D and Expelled it Outside the Tumor Cells, Without Effects on KRAS^WT Cells

[0405] To investigate the spectrum of human malignancies that could be susceptible to PIGR- mediated dlgA transcytosis, PIGR expression in tumors in TCGA datasets was analyzed. A clear dichotomy between epithelial malignancies and B-cell lymphoma, which express relatively high PIGR mRNA levels was found; and non-epithelial tumors such as melanoma or glioblastoma, which express lower levels (FIG. 7A). To test whether antigen-specific dlgA, and not non-specific dlgA (FIG. 7B and FIG. 7C), could target specific molecules in the cytoplasm of different carcinomas, targeting KRAS^G12D was first focused on, a mutational hotspot present in >4% of human cancers (Consortium, A.P.G. (2017) Cancer Discov 7: 818-831). Recombinant KRAS^G12D- specific antibodies produced on a dlgA or monomeric IgG4 backbone, using identical variable heavy and variable light sequences (FIG. 8A - FIG. 8C), specifically recognized ectopic or endogenous mutant KRAS^G12D, but not other KRAS mutations, in Western-blot analysis (FIG. 1A; FIG. 8D). However, only mutation-specific dlgA, but not IgG, penetrated KRAS^G12D-mutated lung cancer cells (FIG. IB, left), where mutation-specific, but not control dlgA, targeted KRAS (FIG. IB, right). Consistently, KRAS^G12D-specific dlgA penetrated OVCAR3 cells transduced with KRAS^WI or KRAS^G12D fused to photoactivatable (PA)m-Cherry fluorescent protein (Nan, X., et al. (2015) Proc Natl Acad Set USA 112:7996-8001), but only disrupts cytoplasmic localization and distribution of intracellular KRAS^G12D (FIG. 1C). Notably, mutant KRAS was not only neutralized inside tumor cells, but also expelled outside the cell through transcytosis, as evidenced by co-occurrence of KRAS^G12D with secretory IgA in the supernatant of KRAS^G12D-PAmCherry- transduced OVCAR3 cells upon treatment with KRAS^G12D-specific dlgA (FIG. ID), with decreased intracellular KRAS^G12D (FIG. IE and FIG. 8E). Furthermore, PAmCherry fragments, fused to KRAS^G12D, were only found in the supernatant of tumor cells treated with KRAS^G12D- specific dlgA in 3 independent experiments (FIG. IF, left). In contrast, KRAS^G12D was not found in supernatants upon treatment with KRAS^G12D-specific IgG4, irrelevant IgA or vehicle (FIG. ID and FIG. IF, left). As expected, PIGR was identified in the supernatants of cells treated with antigen-specific or control dlgA (FIG. IF, right). Together, these results indicate that tumor cellpenetrating dlgA can indeed target specific mutations in KRAS inside tumor cells, resulting in intracellular decreased levels and expelling the oncodriver outside the tumor cell, without obvious effects in KRAS unmutated epithelial cells.

Example 2 KRAS^G12D and Mutation-Specific dlgA Were Found in the Same Endosomal Compartments Upon Transcytosis

[0406] To confirm bona fide unidirectional transcytosis, a classical transwell system was used where tumor cells prevent the access of dlgA delivered to the upper chamber into the basal chamber, unless it transcytoses through PIGR⁺ tumor cells (Oztan, A., et al. (2008) Methods Mol Biol 440: 157-170). As shown in FIG. 1G and FIG. 8F, an accumulation of KRAS^G12D antigen in the basal chamber was present when KRAS^G12D-mutant tumor cells were treated with antigenspecific dlgA, but not in wild-type tumor cells, tumor cells with other mutations, or upon PIGR ablation (FIG. 1G and FIG. 8F). Also, only traces of antigen were found in the upper chamber, where dlgA was added and found in similar amounts, supporting that KRAS^G12D-specific dlgA undergoes "true" transcytosis through PIGR⁺ tumor cells. Accordingly, high-resolution confocal microscopy confirmed that aggregates of KRAS^G12D-specific dlgA co-localize with KRAS^G12D- PamCherry inside tumor cells, while the same antibody on an IgG4 backbone cannot penetrate tumor cells or alter the preferential location of mutant KRAS on the cell surface (FIG. 2A).

[0407] To understand the dynamics of interactions between antigen-specific dlgA and mutant KRAS inside tumor cells, early (RAB5A⁺), late (RAB7A⁺) and recycling (RAB8A⁺/RAB11A⁺) endosomes^15,16 in tumor cells treated with KRAS^G12D-specific dlgA or IgG were immunoprecipitated. As expected, given the lack of penetration into tumor cells, KRAS^G12D- specific IgG was undetectable in any endosomes, while dlgA transcytosed through early and late endosomes (FIG. 2B) Consistent with known recycling pathways that prevent proteasomal degradation (Schmick, M., et al. (2015) Trends Cell Biology 25: 190-197), mutant KRAS was primarily found in RAB8A⁺/RAB11A⁺ recycling endosomes when tumor cells were treated with vehicle or antigen-specific IgG (FIG. 2B). In contrast, treatment with KRAS^G12D-specific dlgA concentrated mutant KRAS on the same endosomes through which dlgA traffics inside tumor cells (FIG. 2B), indicated that transcytosing dlgA encounters the antigen on the cell membrane and hauls it in endosomes, eventually expelling the target through secretory IgA. Although dlgA traffics through endosomes, dlgA retains its capacity to specifically target intracellular antigens; at least those that are located near the cell membrane. [0408] Consistent with capture and extracellular disposal of KRAS^G12D, treatment of KRAS^G12D- transduced cancer cells with mutation-specific dlgA inhibited tumor cell proliferation, without effects on the same cells transduced with KRAS^WT or untransduced ovarian cancer cells (FIG. 3A to FIG. 3C). As expected, treatment of endogenously mutated KRAS^G12D lung cancer cells with mutation-specific dlgA also inhibited tumor cell proliferation (FIG. 3D), while neither antigen specific or control dlgA showed any effects on the proliferation of non-malignant HEK293T cells (FIG. 3E). Of note, antigen-specific dlgA dampened proliferation of KRAS^G12D cancer cells without causing apoptosis (FIG. 3F). Therefore, antigen-specific dlgA can expel oncodrivers outside tumor cells by preventing endosomal recycling, resulting in KRAS^G12D accumulation in the same endosomal compartments where dlgA traffics.

Example 3 KRAS^G12D-Specific dlgA Specifically Abrogated the Progression of Mutant Tumors In Vivo

[0409] To demonstrate the effectiveness of KRAS^G12D-specific dlgA in vivo, intra-tumoral infusions of different treatments in KRAS^G12D-transduced OVCAR3 tumor-bearing Rag\~ ~ mice was performed. It had previously been reported that irrelevant dlgA dampens the RAS pathway by upregulating DUSP phosphatases that dephosphorylate ERK1/2, while activating inflammatory pathways associated with IFN and TNF signaling, as well as pro-apoptotic pathways linked to ER stress (Biswas, S., etal. (2021) Nature 591 :464-470; Mandal, G., etal. (2022) Cancer Res 82:859- 871). Accordingly, non-specific dlgA delayed the growth of established ovarian tumors. However, the anti -tumor effects of KRAS^G12D-specific dlgA were significantly greater (FIG. 4A and FIG. 4B), with no obvious signs of toxicity in any treated mice. Consistently with its inability to penetrate tumor cells, the same variable heavy and light chains on an IgG4 backbone only elicit a non-statistically significant trend towards tumor reduction, potentially attributable to neutralization of extracellular vesicles (FIG. 4B and FIG. 9A and FIG. 9B). Supporting the specificity of this intervention, no effects on tumor growth were elicited in tumor cells transduced with KRAS^W, (FIG. 4C and FIG. 9A and FIG. 9C), beyond the non-antigen-specific effects of IgA transcytosis.

[0410] Tumor growth was dependent on KRAS^G12D because, as reported (Wang X, et al. (2022) J Med Chem 65:3123-3133), the KRAS^G12D-selective inhibitor MRTX1133, currently under preclinical development (Wang X, et al. (2022) J Med Chem 65:3123-3133), also elicited significant delays in tumor growth, although daily intraperitoneal administration (20 injections) were required (FIG. 9A - FIG. 9C).

[0411] Selective effectiveness of antigen-specific dlgA was recapitulated when antibodies were intraperitoneally administered in KRAS^G12D tumor-bearing NSG mice (FIG. 4D and FIG. 10A and FIG. 10B), ruling out the requirement of functional myeloid cells or NK lymphocytes in this model, while supporting systemic distribution of dlgA. Again, 20 (daily) doses of intraperitoneal MRTX1133 or 5 injections of KRAS^G12D-specific dlgA both delayed tumor progression beyond the effects of irrelevant IgA (FIG. 4D and FIG. 10B). Correspondingly, human IgA was identified in resected tumors (FIG. 4E), confirming trafficking of antigen-specific dlgA to tumor beds. The results of these experiments support the potential of tumor cell-penetrating dlgA to specifically target mutated oncodrivers inside carcinoma cells in vivo.

Example 4

Lung Tumors Quasi-Universally Expressed PIGR and Lung Tumors Quasi-Universally Express PIGR and Were Highly Sensitive to Mutant Oncodriver-Neutralizing dlgA

[0412] To demonstrate the capacity of dlgA to target other human tumors that are spontaneously driven by KRAS^G12D, as opposed to ectopic KRAS expression, non-small cell lung cancer (NSCLC), which is frequently driven by mutant KRAS, including KRAS^G12D, was first focused on. Analyses of 30 human lung cancer tissues including squamous cell carcinomas and adenocarcinomas, showed PIGR expression in all tumors, along with spontaneous production of IgA and IgG at tumor beds bound to tumor epithelial tissues as well as to stroma (FIG. 5A), without differences for histological subtypes (FIG. 11 A). Notably, PIGR and tumor-bound IgA density, IgG coating of tumor cells, or PIGRTgA interactions were all associated with stronger T cell accumulation (FIG. 5B) Therefore, demonstrating the effectiveness of mutation-specific dlgA against lung carcinomas endogenously driven by KRAS^G12D was prioritized. As shown in FIG. 5C and FIG. 5D, 5 intraperitoneal injections of KRAS^G12D-specific dlgA, or 20 daily treatments of MRTX1133 at high dose (200 pg) (Wang, X., et al. (2022) J Med Chem 65:3123- 3133), effectively abrogated the progression of established A427 NSCLC, while the same antibody on an IgG4 backbone had negligible effects (FIG. 5C and FIG. 5D; FIG. 10B and 10C). Accordingly, treatment with both KRAS^G12D-specific dlgA and MRTX1133 decreased ERK1/2 phosphorylation in A427 cells in a time-dependent manner (FIG. 5E). Anti-tumor effects were not limited to this tumor model, because established KRAS^G12D-mutant SK-LU-1 lung cancers also responded to KRAS^G12D-specific dlgA with comparable effectiveness, although they were more resistant to MRTX1133 (FIG. 5C and FIG. 5F; FIG. 11B & FIG. 11D). These experiments support the potential of dlgA-mediated intracellular targeting of KRAS^G12D to abrogate the progression of spontaneously mutated NSCLCs, in a mutation-specific manner and without off- target effects in unmutated epithelial cells.

[0413] dlgAtranscytosis sensitizes tumor cells to T cell-mediated killing (Biswas, S., etal. (2021) Nature 591 :464-470). To define the contribution of this mechanism, a syngeneic, immunogenic KRAS^G12D-mutant KPMSH2^KIN lung tumors, generated by cloning lung cancer cells from C57/BL6 mice with inducible mutations was utilized, activated using intra-nasal adenoviral Cre; plus restoring MSH2 through lentiviral transduction. As expected, dlgA targeting KRAS^G12D also elicited a significant delay in tumor growth (FIG. 5G). Interestingly, anti-tumor effects in this immunogenic system were dependent on CD8 T cells (FIG. 5G), highlighting the complexity of a coordinated adaptive immune response. Further supporting the specificity of dlgA for cognate antigen, similar anti-tumor effects were not observed upon administration of dlgA targeting a different mutation (IDH1^R132H) (FIG. 5G). Corresponding effects were observed in another syngeneic KRas^G12D breast cancer model (Brpkpl lO FIG. HE) (Allegrezza, M.J., et al. (2016) Cancer Res 76:6253-6265).

Example 5 dlgA Was Effective Against Mutations Located Deeper into the Cytoplasm of Tumor Cells, in a PIGR-Dependent Manner

[0414] To demonstrate the feasibility of targeting additional intracellular antigens, located deeper into the cytoplasm of tumor cells, and also the potential of using dlgA to target other epithelial cancers different from ovarian and lung carcinomas, dlgAl or IgG4 specifically targeting the cytoplasmic R132H mutation in isocitrate dehydrogenase 1 (IDH ), a common hotspot in multiple human tumors (FIG. 6A; FIG. 8A- FIG. 8C; TABLE 5A - TABLE 5Z) (Capper D, et al. (2010) BrainPathol 20:245-254; Calvert, A.E., etal. (2017) Cell Rep 19: 1858-1873). To further evaluate the role of PIGR abundance for dlgA effectiveness, isogenic II)H1 ^V[ and IDH1⁺^^31R HCT116 colon cancer cells were procured, which express low PIGR levels, and transduced with PIGR, resulting in expression levels comparable to those found in multiple carcinoma cell lines (FIG. 6A). Low PIGR expression abrogated the non-specific anti-tumor effects of irrelevant IgA in this system (FIG. 6B - FIG. 6D). Similar to KRAS^G12D targeting, IDHl^R132H-specific dlgA delayed tumor growth in mutant tumors, without effect in the absence of IDH1^R132H mutations (FIG. 6C, FIG. 6D). Notably, anti -tumor effects were dependent on PIGR expression in tumor cells, because the administration of IDHl^R132H-specific dlgA resulted in a 3.7-fold reduction in tumor growth, compared to vehicle, when PIGR -transduced IDH1^R132HHCT116 cells were treated, compared to a 1.8-fold reduction in low-PIGR-expressing parental IDH1^R132HHCT116 colon tumors (FIG. 6B, FIG. 6C, FIG. 6E). Importantly, anti -turn or effects were again mutation-specific, because a comparable reduction in tumor growth was observed when mice with IDH1^WT tumors were treated with irrelevant IgA or IDHl^R132H-specifc dlgA (FIG. 6F). Dimerization of mutation-specific IgA was also required because the monomeric version of the same IDHl^R132H-specific IgA showed no significant antitumor effects (FIG. 6G). Together these results support the strategy of using antigen-specific dlgA to target carcinomas of multiple histological origins and different mutated oncodrivers. These data also support the feasibility of targeting tumors despite low PIGR expression, albeit with possibly decreased effectiveness.

[0415] Collectively, these data demonstrate the feasibility of specifically targeting commonly mutated hotspots in oncogenes driving malignant progression in many human carcinomas, using antigen-specific dlgA that transcytoses through all epithelial cells but only targets mutated malignant cells.

[0416] These results further confirm that PIGR-mediated transcytosis of dlgA decreases ERK1/2 phosphorylation and thwarts tumor growth also in non-gynecological malignancies, as we previously reported (Biswas S, et al. (2021). Nature 591 :464-470). PIGR-dependent transcytosis occurs in at least non-small cell lung and colorectal cancers. Given that PIGR is expressed in most epithelial malignancies, but only at lower levels in non-epithelial cancers (Pascal V, et al. (2012) Haematologica 97: 1686-1694), this mechanism may be relevant for most human carcinomas. PIGR-mediated dlgA transcytosis progresses through endosomal trafficking but their route of trafficking may slightly differ in malignant cells than in non-malignant cells (Fan, X., et al. (2021) IntJMol Set 22). Despite trafficking through endosomes, dlgA retained its capacity to specifically target intracellular antigens. This activity was not limited to mutated oncodrivers that are located near the cell membrane, such as KRAS, but also mutated oncogenes such as IDH1, which is located deeply inside the cytoplasm. Novel studies may determine whether other commonly mutated oncogenes such as PI3K or AKT, or immunosuppressive intracellular pathways such as IDO, could be more effectively targeted with dlgA than with small molecule inhibitors.

[0417] dlgA-mediated targeting, along or in combination with small molecules, could have significant advantages, compared to small molecules: First, these results underscore the specificity of this approach. Second, although the half-life of IgA (~6 days) (Leusen, J.H. (2015) Mol Immunol 68:35-39) is lower than that of IgG, modifications in glycosylation or attaching an albumin-binding domain to the heavy or light chain could increase their persistence, which is nevertheless much longer than for small molecule inhibitors, as supported by the results disclosed herein (Sterlin, D., et al. (2021) Pharmacology 106:9-19; Meyer, S., et al. 8:87-98). Third, dlgA expels the mutated oncogene outside tumor cells, which is obviously advantageous, compared to temporary neutralization. Finally, the prospect of oral secretory IgA treatment (Richards, A., et al. (2022) Human vaccines & immunotherapeutics 18), could make the various aspects of the intervention ideal against tumors of the digestive tract. A rationale is disclosed herein for using dlgA as a new form of immunotherapy to target intracellular oncodrivers, which could open multiple new avenues to treat otherwise undruggable carcinomas. [0418] Although the dlgA treatments did not fully eliminate xenograft tumors, only 5 injections were administered and only established (i.e., palpable) tumors were treated. Second, the effect could be enhanced in immunocompetent hosts, since oncodrivers delivered outside the tumor cell by antigen-specific dlgA could be more effectively taken-up by CD351⁺ antigen-presenting cells, enhancing protective immunity in patients with specific HLA alleles.

[0419] Finally, an additional issue regarding the future translatability of dlgA is potential toxicity. In support of the clinical potential of the disclosed approach, oral IgA-IgG treatment has already been safely used to treat children with chronic non-specific diarrhea (Casswall, T.H., et al. (1996) Acta Paediatr 85: 1126-1128), and polyclonal antibody preparations containing >20% IgA can be safely administered in patients with severe pneumonia (Welte, T., etal. (20 IS) Intensive Care Med 44:438-448). In addition, mutation-specific dlgA had no effect on wild-type cells, while dimeric IgA is the predominant Ig at mucosal secretions (Woof, J.M., et al. (2011) Mucosal Immunol 4:590-597). Therefore, IgA administration is not expected to cause on-target, off-tumor toxicity. Furthermore, FDA-approved KRAS^G12C small molecule inhibitors already elicit grade 3-4 toxicity in >11% of patients. These results provide a rationale for developing dlgA-based therapeutics that specifically target intracellular antigens in human cancer patients.

[0420] Regarding FIGS. 1A to 6G, recombinant KRAS^G12D-specific IgAl and IgG4 antibodies comprised the aKRas^G12D IgAl heavy chain amino acid sequence of SEQ ID NO: 87 and KRAS^G12D IgG4 antibodies comprised the aKRas^G12D IgG4_Heavy Amino acid sequence of SEQ ID NO:88, the aKRas^G12D Kappa light chain amino acid sequence of SEQ ID NO:89 and the j- chain with amino acid sequence of SEQ ID NO:90.

[0421] Recombinant IDHl^R132H-specific IgAl/IgG4 antibodies comprised the aIDHl^R132H IgAl heavy amino acid sequence of SEQ ID NO:91, the aIDHl^R132H IgG4_heavy amino acid sequence of SEQ ID NO:92, the aIDHl^R132H Kappa light amino acid sequence of SEQ ID NO:93, and the j-chain of amino acid sequence of SEQ ID NO:94

Rationale for Examples 6 - 7

[0422] Producing a recombinant dimeric IgA may be more challenging than producing a recombinant monomeric IgG. In addition, the half-life of IgG4 in patients is ~20 days, compared to ~a week for IgA, and target occupancy could last for 85 days (Leusen, J.H. Mol Immunol 68, 35-39 (2015); Topalian, S.L., et al. N Engl J Med 366, 2443-2454 (2012)). A novel human IgG4 Abs was therefore generated with the same VH/VL used in the above discussed dlgA. To elicit PIGR-mediated transcytosis a known 25mer that binds to PIGR and promotes transcytosis in vitro and identified through the screening of a phage display library was used (Braathen, R., et al. (2006). J Biol Chem 281, 7075-7081; Borrok, M.J., et al. (2018). JCI Insight 3). This peptide was connected to the C-terminus of the Fc domain, using a short glycine-serine spacer (FIG. 12A). It was then confirmed that modified IgG was capable of delaying tumor growth.

Example 6

Modifications in the Fc Domain of IgG4 Allowed PIGR-Dependent Internalization

[0423] Referring now to FIG. 12B and FIG. 12C, to define the effectiveness of treating KRAS^G12D-mutant tumors using a modified IgG4 that triggers PIGR-mediated transcytosis through a short peptide domain, a novel syngeneic, immunogenic KRAS^G12D-mutant KPMSH2^KIN lung tumor model was generated. The model was generated by cloning lung cancer cells from C57/BL6 mice with inducible mutations, activated using intra-nasal adenoviral Cre, in mice carrying latent mutations (TP53^flx/flxL-Stop-L KRAS^G12DMSH2^flx/flx). Note that the KRAS^G12D Ag is identical in mice and humans. To prevent further antigenic drifting of these already immunogenic tumors, MSH2 was restored through lentiviral transduction. Immunocompetent B6 mice were challenged into the flank and treatments with either dlgA or modified IgG (100 pg/inj ection, IP) were administered every 4 days (5 injections, total). The results in FIG. 12C show that dimeric IgA targeting KRAS^G12D (red line - circles) elicited a significant delay in tumor growth, compared to control mice receiving PBS (black line - boxes). Also, the PIGR-triggering IgG4 that uses the same scFv (blue line - triangle) was as effective as the dimeric IgA version of the antibody, supporting the potential of this formulation as an alternative to the production of IgA, which is less efficient, compared to producing recombinant IgG.

[0424] As shown in FIG. 13A and FIG. 13B, PIGR-binding IgG penetrated epithelial cancer cells, and underwent bona fide transcytosis, because predominant signal of antigenic KRAS^G12D was found in the upper chamber of a transwell system, co-IPed with Ag-specific antibodies. These results demonstrate that IgGs modified through the addition of this PIGR-binding peptide had the capacity to transcytose through both mouse Pigr and human PIGR8, which is useful in understanding how the antibodies are distributed in hosts that spontaneously express Pigr+ healthy mucosal cells, and that PIGR-binding IgG4 antibodies could be advantageously used instead of dlgA to target cytosolic antigens.

Example 7

Generation and Testing of Modified Human GTP-bound KRAS-specific Abs

[0425] To generate new antibodies specifically targeting GTP-bound mutant KRAS (the active, oncogenic conformation), different complementary approaches were employed. First, a tailored mutagenesis method was applied to modify by >20% the CDR regions in the VH and VL chains of the KRAS^G12D-specific IgA previously used, by modifying a subset of amino acids consistently associated with affinity improvements in a large data set of affinity -matured antibodies (Gonzalez- Munoz, A., et al. (2012). MAbs 4, 664-672). [0426] Two modified recombinant antibodies on an IgG4 backbone, connected to the PIGR- binding peptide, were generated. The first (IgG#l) had the heavy chain (with constant domain, spacer, and PIGR binding domain) set forth in SEQ ID NO: 10, and had the light chain set forth in SEQ ID NO: 14. The second (IgG#2) had the heavy chain (with heavy constant domain, spacer, and PIGR binding domain) set forth in SEQ ID NO: 18, and had the light chain set forth in SEQ ID NO:22. In addition, the sequence of a known mouse KRAS^G12D-specific antibody was humanized into an IGHVl-2*06/IGHJ4*01; IGKV2-40*01/IGKJ4*01 backbone, for which the CDR sequences were also modified by >20%. This anti-mutant KRAS antibody was called IgG#3, and had a heavy chain (with heavy constant domain, spacer, and PIGR binding domain) set forth in SEQ ID NO:96, and had the light chain set forth in SEQ ID NO: 100.

[0427] To compare the effectiveness of these formulations with the modified IgG that uses the VH/VL of a dlgA (termed IgG#0; VH (SEQ ID NO:01) and VL (SEQ ID NO:05), NSG mice (5/group) were treated with palpable KRAS^G12D-driven HEC1A endometrial tumors with the 4 different formulations (FIG. 14A) or PBS. As shown in FIG. 14B, all IgG4 antibodies modified to bind to PIGR reduced tumor growth with similar efficacy.

[0428] As shown in FIG. 14C, a modification by including the PIGR-binding peptide with no GS spacer but preserving the FcRn motifs that are required for IgG persistence in vivo (VH - SEQ ID NO: 124) was also tested. The truncated version also had 9 fewer amino acids on the N-terminus of the Fc domain. However, this modification was less effective (FIG. 14B)

[0429] The GTP bound KRAS-specific antibody (IgG#0) comprised the aKRas heavy _IgG4 + aPIGR peptide with the amino acid sequence of SEQ ID NO:01, and the aKRas^mut Light Kappa with amino the acid sequence of SEQ ID NO:05. Note that in the sequence listed in the present application, a Phe has been added that was not present in the previously disclosed sequence, which was added to produce a more effective recombinant dimeric IgA.

[0430] The GTP bound KRAS-specific antibody (IgG#l) comprised a >20% modification (when compared to IgG#0 (SEQ ID NO:01 and SEQ ID NO: 05)) in each of the 3 CDRS in the aKRas heavy _IgG4 + aPIGR peptide (SEQ ID NO: 10) and in each of the 3 CDRs in the aKRasmut Light Kappa (SEQ ID NO: 14).

[0431] The GTP bound KRAS-specific antibody (IgG#2) comprised a >20% modification (when compared to IgG#l (SEQ ID NO: 10 and SEQ ID NO: 14) in each of the 3 CDRs in the aKRas heavy _IgG4 + aPIGR peptide (SEQ ID NO: 18) and in each of the 3 CDRs in the aKRasmut Light Kappa (SEQ ID NO:22). [0432] The CDR listed in SEQ ID NO:02 and the CDR listed in SEQ ID NO: 120 are the same, but for the insertion of an F (Phe), which was added to produce a more effective recombinant dimeric IgA.

[0433] A humanized antibody (IgG#3) was created by modifying the CDRs of a known mouse Ab targeting mutant KRAS to generate an anti-mutant KRAS antibody comprising a VH with constant heavy domain, spacer, and PIGR binding domain peptide) having the sequence of SEQ ID NO: 96 and VL having the sequence of SEQ ID NO: 100.

[0434] The IgG#3 antibody was then modified (IgG#4) to include a different human IgGbackbone and included a VH (with constant heavy domain, spacer, and PIGR binding domain peptide) having the sequence of SEQ ID NO: 104, and a VL having the sequence of SEQ ID NO: 108.

Example 8 Additional Active Ras-GTP-Specific IgG Human Antibodies

[0435] Generation of additional active Ras GTP-specific human antibodies was sought by using recombinant KRAS-^G12D mutant proteins from BPS Bioscience, which were loaded with the non- hydrolysable GTP analog, GppNHp (guanosine 5'-P,y-imido triphosphate). The conformations of GppNHp-bound KRas mutants were equivalent to those of the GTP -bound forms with resistance to y-phosphate hydrolysis (Shin SM, et al. (2017). Nat Commun. 8: 15090). As a control, recombinant WT KRAS proteins from the same company, which were loaded with GDP, were used.

[0436] Two different synthetic human scFv libraries (Hyperimmune scFv (lelO diversity); and Ancestral scFv (le9 diversity)) were screened for positive signals for GppNHp -bound mutant KRAS, but not GDP -bound WT KRAS. Eventually, 8 different clones showed differential signals >2-fold. Sequencing of these scFv showed that they corresponded to 3 different sequences. These 3 scFv sequences were used to generate modified IgG4 antibodies, in which the Fc domain was connected to a PIGR-signaling peptide, to trigger PIGR-mediated transcytosis and therefore intracellular uptake of the antibody, to allow neutralization of the cognate antigen (GTP-bound oncogenic mutant KRAS) inside the cytosol of tumor cells.

[0437] Antibody IgG#5 (aka SEL-39 - IgG4 #1) comprised an a-GTP -bound KRAS^G12D IgG4 VH with an amino acid sequence of SEQ ID NO:26 and VL with an amino acid sequence of SEQ ID NO:33. Antibody IgG#6 (aka SEL-39 - IgG4 #2) comprised an a-GTP -bound KRAS^G12D IgG4 VH with an amino acid sequence of SEQ ID NO:37 and VL with an amino acid sequence of SEQ ID NO:44. Antibody IgG#7 (aka SEL-39 - IgG4 #3) comprised an a-GTP -bound KRAS^G12D IgG4 VH with an amino acid sequence of SEQ ID NO: 50 and VL with an amino acid sequence of SEQ ID NO:57. Example 9 Additional Active Ras-GTP-Specific dlgA Human Antibodies

[0438] In congruency with the results of Examples 1 -5 above, the sequences in Example 8 above, served as a basis to prepare three anti KRAS^G12D antibodies on a dimeric IgA backbone with 2 monomers connective by a J chain, which showed that dimeric IgA has the capacity to penetrate PIGR⁺ tumor cells, and therefore neutralize intracellular targets. The first dlgA antibody (aka SEL-39 - dlgA #1) comprised SEQ ID NO:63 as the IgA (a-GTP -bound KRAS^G12D IgAl VH) and SEQ ID NO:67 as the IgA (a-GTP -bound KRAS^G12D IgAl VL). The second dlgA antibody (aka SEL-39 - dlgA #1) comprised SEQ ID NO:71 as the IgA (a-GTP -bound KRAS^G12D IgAl VH) and SEQ ID NO:75 as the IgA (a-GTP -bound KRAS^G12D IgAl VL. The third dlgA antibody (aka SEL-39 - dlgA #1) comprised SEQ ID NO:79 as the IgA (a-GTP -bound KRAS^G12D IgAl VH) and SEQ ID NO: 83 as the IgA (a-GTP-bound KRAS^G12D IgAl VL.

TABLE 4 - Sequences

Ill

TABLE 5A - Details of statistical methods and associated P values related to FIG. 3A TABLE 5B - Details of statistical methods and associated P values related to FIG. 3B

TABLE 5C - Details of statistical methods and associated P values related to FIG. 3C

TABLE 5D - Details of statistical methods and associated P values related to FIG. 3D

TABLE 5E - Details of statistical methods and associated P values related to FIG. 3E TABLE 5F - Details of statistical methods and associated P values related to FIG. 3F

TABLE 5G - Details of statistical methods and associated P values related to FIG. 4B TABLE 5H - Details of statistical methods and associated P values related to FIG. 4C

TABLE 51 - Details of statistical methods and associated P values related to FIG. 4D

TABLE 5J - Details of statistical methods and associated P values related to FIG. 5B

TABLE 5K - Details of statistical methods and associated P values related to FIG. 5D

TABLE 5L - Details of statistical methods and associated P values related to FIG. 5F

TABLE 5M - Details of statistical methods and associated P values related to FIG. 5G

TABLE 5N - Details of statistical methods and associated P values related to FIG. 6C

TABLE 50 - Details of statistical methods and associated P values related to FIG. 6D

TABLE 5P- Details of statistical methods and associated P values related to FIG. 6E

TABLE 5Q - Details of statistical methods and associated P values related to FIG. 6F

TABLE 5R - Details of statistical methods and associated P values related to FIG. 6G

TABLE 5S - Details of statistical methods and associated P values related to FIG. 9B

TABLE 5T - Details of statistical methods and associated P values related to FIG. 9C

TABLE 5U - Details of statistical methods and associated P values related to FIG. 10B

TABLE 5V - Details of statistical methods and associated P values related to FIG. 11A

TABLE 5X - Details of statistical methods and associated P values related to FIG. 11C

TABLE 5Y - Details of statistical methods and associated P values related to FIG. 11D

TABLE 5Z - Details of statistical methods and associated P values related to FIG. HE

Claims

IX. CLAIMS What is claimed is:

1. An anti-mutant KRAS antibody, comprising: an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) peptide binding domains, wherein the antibody recognizes the GTP -bound active form of KRAS.

2. The anti-mutant KRAS antibody of Claim 1, wherein the antibody comprises: a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and a variable heavy chain region (VH) comprising 3 CDRs and a constant heavy chain region, wherein the VH is linked to the constant heavy chain region, and wherein the constant heavy chain region is linked to the PIGR biding domain.

3. The anti-mutant KRAS antibody of Claim 2, wherein each CDR in the VL comprise the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

4. The anti-mutant KRAS antibody of Claim 2, wherein a CDR in the VL comprises a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO: 07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

5. The anti -mutant KRAS antibody of Claim 2, wherein each CDR in the VH comprise the sequence set forth in any one of SEQ ID NO:02, SEQ ID NO:03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

6. The anti-mutant KRAS antibody of Claim 2, wherein a CDR in the VH comprises a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence in any one of SEQ ID NO:02, SEQ ID NO:03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

7. The anti-mutant KRAS antibody of Claim 3, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO: 08; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

8. The anti-mutant KRAS antibody of Claim 5, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO: 04; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO: 03, and a CDR having the sequence set forth in SEQ ID NO: 04; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:97, a CDR having the sequence set forth in SEQ ID NO: 98, and a CDR having the sequence set forth in SEQ ID NO: 99; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107.

9. The anti-mutant KRAS antibody of Claim 2, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO: 08; and wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO:04.

10. The anti -mutant KRAS antibody of Claim 2, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO: 08; and wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO: 03, and a CDR having the sequence set forth in SEQ ID NO:04.

11. The anti -mutant KRAS antibody of Claim 2, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17; and wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13.

12. The anti-mutant KRAS antibody of Claim 2, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21; and wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25.

13. The anti -mutant KRAS antibody of Claim 2, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:97, a CDR having the sequence set forth in SEQ ID NO: 98, and a CDR having the sequence set forth in SEQ ID NO: 99; and wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103.

14. The anti-mutant KRAS antibody of Claim 2,

(i) wherein the VL comprises the sequence set forth in SEQ ID NO:05, and wherein the VH, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO:01 or SEQ ID NO: 114; or

(ii) wherein the VL region comprises the sequence set forth in SEQ ID NO: 14, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO: 10; or

(iii) wherein the VL region comprises the sequence set forth in SEQ ID NO:22, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO: 18; or

(iv) wherein the VL region comprises the sequence set forth in SEQ ID NO: 100, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO:96; or

(v) wherein the VL region comprises the sequence set forth in SEQ ID NO: 108, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO: 104.

15. The anti -mutant KRAS antibody of Claim 2, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107; and wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

16. The anti -mutant KRAS antibody of Claim 2, wherein the VH, the constant heavy chain region, a GS-based spacer, and the PIGR binding domain comprises the sequence set forth in SEQ ID NO:26, SEQ ID NO:37 or SEQ ID NO:50, and wherein the VL comprises the sequence set forth in SEQ ID NO:33, SEQ ID NO:44 or SEQ ID NO: 57.

17. The anti -mutant KRAS antibody of Claim 2, wherein each CDR in the VH comprises the sequence set forth in any one of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID N0:31, SEQ ID NO:32, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO 53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56.

18. The anti -mutant KRAS antibody of Claim 2, wherein each CDR in the VL comprises the sequence set forth in any one of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:49, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO: 124, SEQ ID NO: 125, and SEQ ID NO: 126.

19. The anti -mutant KRAS antibody of Claim 17, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:27 or SEQ ID NO:28, a CDR having the sequence set forth in SEQ ID NO:29 or SEQ ID NO:30, and a CDR having the sequence set forth in SEQ ID NO:31 or SEQ ID NO:32; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39, a CDR having the sequence set forth in SEQ ID NO:40 or SEQ ID NO:41, and a CDR having the sequence set forth in SEQ ID NO: 42 or SEQ ID NO:43; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:51 or SEQ ID NO:52, a CDR having the sequence set forth in SEQ ID NO:53 or SEQ ID NO:54, and a CDR having the sequence set forth in SEQ ID NO:55.

20. The anti -mutant KRAS antibody of Claim 18, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:34, a CDR having the sequence set forth in SEQ ID NO:35, and a CDR having the sequence set forth in SEQ ID NO:36; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 124, a CDR having the sequence set forth in SEQ ID NO: 125, and a CDR having the sequence set forth in SEQ ID NO: 126; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:45 or SEQ ID NO:46, a CDR having the sequence set forth in SEQ ID NO:47 or SEQ ID NO:48, and a CDR having the sequence set forth in SEQ ID NO:49; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:58 or SEQ ID NO:59, a CDR having the sequence set forth in SEQ ID NO:60 or SEQ ID NO:61, and a CDR having the sequence set forth in SEQ ID NO:62.

21. The anti -mutant KRAS antibody of Claim 2,

(i) wherein the VL region comprises the sequence set forth in SEQ ID NO:33, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO:26; or

(ii) wherein the VL region comprises the sequence set forth in SEQ ID NO:44, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO:37; or

(iii) wherein the VL region comprises the sequence set forth in SEQ ID NO:57, and wherein the VH region, the constant heavy chain region, a GS-based spacer, and a PIGR peptide binding domain comprise the sequence set forth in SEQ ID NO: 50.

22. The anti-mutant KRAS antibody of Claim 2, wherein each CDR in the VL comprises the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86.

23. The anti -mutant KRAS antibody of Claim 2, wherein each CDR in the VH comprise, the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

24. The anti-mutant KRAS antibody of Claim 1, wherein the antibody comprises a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and a variable heavy chain region (VH) comprising 3 CDRs, wherein the VH is linked to a constant heavy chain region.

25. The anti -mutant KRAS antibody of Claim 24, wherein the VL comprises the sequence set forth in SEQ ID NO:67, SEQ ID NO:75; or SEQ ID NO: 83; and wherein the VH linked to the constant heavy chain region comprise the sequence set forth in SEQ ID NO:63, SEQ ID NO:71, or SEQ ID NO:79.

26. The anti-mutant KRAS antibody of Claim 24, wherein the constant heavy chain region is linked to the one or more PIGR biding domains.

27. The anti-mutant KRAS antibody of Claim 25, wherein the constant heavy chain region is linked to a PIGR binding domain by a spacer.

28. The anti -mutant KRAS antibody of any preceding claim, wherein the binding of the one or more PIGR binding domains to PIGR on a cell triggers transcytosis of the antibody into the cell.

29. The anti -mutant KRAS antibody of any preceding claim, wherein the IgG backbone comprises an IgGl backbone, an IgG2 backbone, an IgG3 backbone, or an IgG4 backbone.

30. An anti -mutant KRAS antibody, comprising: a dimeric IgA backbone comprising two monomers, wherein each of the monomers comprises a variable light chains region (VL) comprising 3 CDRs and a variable heavy chain region (VH) comprising 3 CDRs, wherein the VH is linked to a constant heavy chain region, and wherein the two monomers are linked together.

31. The anti -mutant KRAS antibody of Claim 30, wherein the two monomers are linked together by a J chain.

32. The anti-mutant KRAS antibody of Claim 30, wherein each CDR in the VL comprises the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86.

33. The anti-mutant KRAS antibody of Claim 30, wherein a CDR in the VL comprises a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86.

34. The anti-mutant KRAS antibody of Claim 30, wherein each CDR in the VH comprise the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

35. The anti-mutant KRAS antibody of Claim 30, wherein a CDR in the VH comprises a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82.

36. The anti-mutant KRAS antibody of Claim 30, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:68, a CDR having the sequence set forth in SEQ ID NO: 69, and a CDR having the sequence set forth in SEQ ID NO: 70, or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:76, a CDR having the sequence set forth in SEQ ID NO:77, and a CDR having the sequence set forth in SEQ ID NO: 78, or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:84, a CDR having the sequence set forth in SEQ ID NO:85, and a CDR having the sequence set forth in SEQ ID NO: 86.

37. The anti-mutant KRAS antibody of Claim 30, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:64, a CDR having the sequence set forth in SEQ ID NO:65, and a CDR having the sequence set forth in SEQ ID NO: 66, or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:72, a CDR having the sequence set forth in SEQ ID NO: 73, and a CDR having the sequence set forth in SEQ ID NO: 74; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:80, a CDR having the sequence set forth in SEQ ID NO:81, and a CDR having the sequence set forth in SEQ ID NO: 82.

38. The anti -mutant KRAS antibody of Claim 30,

(i) wherein the VL comprises the sequence set forth in SEQ ID NO: 67; and wherein the VH linked to the constant heavy chain region comprise the sequence set forth in SEQ ID NO:63; or

(ii) wherein the VL comprises the sequence set forth in SEQ ID NO:75; and wherein the VH linked to the constant heavy chain region comprise the sequence set forth in SEQ ID N0:71; or

(iii) wherein the VL comprises the sequence set forth in SEQ ID NO:83; and wherein the VH linked to the constant heavy chain region comprise the sequence set forth in SEQ ID NO:79.

39. The anti-mutant KRAS antibody of Claim 30, wherein the VH comprises the sequence set forth in any one of SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 119.

40. The anti-mutant KRAS antibody of Claim 30, wherein the VH comprises the sequence set forth in any one of SEQ ID NO: 121, SEQ ID NO: 122, and SEQ ID NO: 123.

41. The anti-mutant KRAS antibody of Claim 30, wherein the VH comprises the sequence set forth in any one of SEQ ID NO:63, SEQ ID NO:71, and SEQ ID NO:79.

42. The anti-mutant KRAS antibody of Claim 30, wherein the VL comprises the sequence set forth in any one of SEQ ID NO:05, SEQ ID NO: 14, SEQ ID NO:22, SEQ ID NO: 100, and SEQ ID NO: 108.

43. The anti-mutant KRAS antibody of Claim 30, wherein the VL comprises the sequence set forth in any one of SEQ ID NO:67, SEQ ID NO:75, and SEQ ID NO:83,

44. The anti-mutant KRAS antibody of Claim 30, wherein the VL comprises the sequence set forth in any one of SEQ ID NO:33, SEQ ID NO:44, and SEQ ID NO: 57.

45. The anti-mutant KRAS antibody of Claim 30, wherein each CDR in the VL comprise the sequence set forth in any one of SEQ ID NO:06, SEQ ID NO:07, SEQ ID NO:08, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111.

46. The anti-mutant KRAS antibody of Claim 30, wherein each CDR in the VH comprise the sequence set forth in any one of SEQ ID NO:02, SEQ ID NO:03, SEQ ID NO:04, SEQ ID NO: 120, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, and SEQ ID NO: 120.

47. The anti-mutant KRAS antibody of Claim 30, wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:06, a CDR having the sequence set forth in SEQ ID NO: 07, and a CDR having the sequence set forth in SEQ ID NO: 08; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 15, a CDR having the sequence set forth in SEQ ID NO: 16, and a CDR having the sequence set forth in SEQ ID NO: 17; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO:23, a CDR having the sequence set forth in SEQ ID NO:24, and a CDR having the sequence set forth in SEQ ID NO:25; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 101, a CDR having the sequence set forth in SEQ ID NO: 102, and a CDR having the sequence set forth in SEQ ID NO: 103; or wherein the VL comprises a CDR having the sequence set forth in SEQ ID NO: 109, a CDR having the sequence set forth in SEQ ID NO: 110, and a CDR having the sequence set forth in SEQ ID NO: 111.

48. The anti-mutant KRAS antibody of Claim 30, wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:02 or SEQ ID NO: 120, a CDR having the sequence set forth in SEQ ID NO:03, and a CDR having the sequence set forth in SEQ ID NO: 04; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 11, a CDR having the sequence set forth in SEQ ID NO: 12, and a CDR having the sequence set forth in SEQ ID NO: 13; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 19, a CDR having the sequence set forth in SEQ ID NO:20, and a CDR having the sequence set forth in SEQ ID NO:21; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO:97, a CDR having the sequence set forth in SEQ ID NO: 98, and a CDR having the sequence set forth in SEQ ID NO: 99; or wherein the VH comprises a CDR having the sequence set forth in SEQ ID NO: 105, a CDR having the sequence set forth in SEQ ID NO: 106, and a CDR having the sequence set forth in SEQ ID NO: 107.

49. The anti-mutant KRAS antibody of any one of Claims 30 - 48, wherein the binding of the J chain to PIGR on a cell triggers transcytosis of the antibody into the cell.

50. The anti-mutant KRAS antibody of any preceding claim, wherein the antibody recognizes the

GTP -bound active form of a mutant KRAS.

51. The anti -mutant KRAS antibody of any preceding claim, wherein the antibody binds intracellular mutant KRAS and promotes the expulsion of the mutant KRAS from the cytoplasm of the cell.

52. The anti-mutant KRAS antibody of any preceding claim, wherein the antibody slows or prevents tumor growth.

53. The anti-mutant KRAS antibody of any preceding claim, wherein the mutant KRAS comprises

KRAS^G12A, KRAS^G12C, KRAS^G12D, KRAS^G12R, KRAS^G12S, KRAS^G12V, KRAS^G12X, KRAS^G13C, KRAS^G13D, KRAS^G13X, KRAS^Q61H, KRAS^Q61L, KRAS^(X,"\ KRAS^Q61R, KRAS^Q61X, KRAS^A146T, KRAS^A146V, KRAS^A146X, or any combination thereof.

54. A pharmaceutical formulation comprising the anti-mutant KRAS antibody of any one of

Claims 1 - 53 and one or more pharmaceutically acceptable carriers.

55. A method of treating a subject having cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical formulation of Claim 54.

56. The method of Claim 55, wherein the cancer is characterized as a mutant KRAS-driven cancer.

57. The method of Claim 56, wherein the cancer is pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

58. The method of Claim 55, wherein following the administering step, PIGR mediated transcytosis is induced.

59. The method of any of Claim 55-58, further comprising administering to the subject a therapeutically effective amount of one or more anti-cancer agents and/or anti-cancer therapies.

60. The method of Claim 55, wherein following the administering step, (i) the risk of developing metastases is prevented and/or decreased, (ii) the survival of the subject is prolonged, (iii) the subject's quality of life is enhanced and/or improved, (iv) the likelihood of surgical intervention is reduced and/or minimized, (v) the size of one or more tumors in the subject is reduced and/or decreased, (vi) one or more tumors in the subject are eliminated, (vii) normal metabolism of one or more organ systems in the subject are improved and/or restored, (viii) one or more aspects of cellular homeostasis and/or cellular functionality, and/or metabolic dysregulation are restored and/or improved, or (ix) any combination thereof.