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NZ729451B2 - Antibodies, compositions, and uses - Google Patents
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NZ729451B2 - Antibodies, compositions, and uses - Google Patents

Antibodies, compositions, and uses Download PDF

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Publication number
NZ729451B2
NZ729451B2 NZ729451A NZ72945115A NZ729451B2 NZ 729451 B2 NZ729451 B2 NZ 729451B2 NZ 729451 A NZ729451 A NZ 729451A NZ 72945115 A NZ72945115 A NZ 72945115A NZ 729451 B2 NZ729451 B2 NZ 729451B2
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NZ
New Zealand
Prior art keywords
seq
set forth
ooooo
antibody agent
agent
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Application number
NZ729451A
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NZ729451A (en
Inventor
Mahiuddin Ahmed
Nai Kong V Cheung
Qi Zhao
Original Assignee
Memorial Sloan Kettering Cancer Center
Filing date
Publication date
Application filed by Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Priority claimed from PCT/US2015/047013 external-priority patent/WO2016033225A2/en
Publication of NZ729451A publication Critical patent/NZ729451A/en
Publication of NZ729451B2 publication Critical patent/NZ729451B2/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53DNA (RNA) vaccination
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/55Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552Veterinary vaccine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14Blood; Artificial blood
    • A61K35/17Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/08Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1018Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against material from animals or humans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/08Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1027Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2299/00Coordinates from 3D structures of peptides, e.g. proteins or enzymes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51Complete heavy chain or Fd fragment, i.e. VH + CH1
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515Complete light chain, i.e. VL + CL
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55Fab or Fab'
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567Framework region [FR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622Single chain antibody (scFv)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732Antibody-dependent cellular cytotoxicity [ADCC]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells

Abstract

The present disclosure describes anti-B7H3 antibody agents and uses relating thereto. Among other things, the present disclosure demonstrates particular immunomodulatory effectiveness of certain such antibodies. The present disclosure further describes particularly high-affinity or otherwise useful antibodies and antibody agents based thereon, including particularly certain humanized and/or affinity matured versions of an 8H9 antibody. In some embodiments, provided antibody agents are useful, for example, in the treatment of cancer. In some embodiments, provided antibody agents are useful in relieving immunosuppression, for example mediated by B7H3-positive cells.

Claims (26)

1. An antibody agent that binds specifically to protein 2Ig-B7H3 or 4Ig-B7H3, wherein the antibody agent comprises: 5 light chain CDR1, CDR2, and CDR3 as set forth in SEQ ID NOs: 34, 36, and 38, respectively, and heavy chain CDR1, CDR2, and CDR3 as set forth in SEQ ID NOs: 58, 60, and 62, tively.
2. The antibody agent of claim 1, comprising an immunoglobulin heavy chain and an 10 immunoglobulin light chain, wherein the antibody agent binds specifically to protein 2Ig-B7H3 or 4Ig-B7H3, and wherein said immunoglobulin light chain variable domain comprises a sequence as set forth in a SEQ ID NO. selected from the group consisting of SEQ ID NO.: 5, 7, and 8, and said globulin heavy chain variable domain comprises a sequence as set forth in a SEQ ID NO. selected from the group consisting of SEQ ID NO.: 13, 15, and 16.
3. The antibody agent of claim 2, wherein: (i) the immunoglobulin light chain is set forth in SEQ ID NO.: 5 and the globulin heavy chain is set forth in SEQ ID NO.: 13; (ii) the immunoglobulin light chain is set forth in SEQ ID NO.: 7 and the 20 immunoglobulin heavy chain is set forth in SEQ ID NO.: 15; or (iii) the immunoglobulin light chain is set forth in SEQ ID NO.: 8 and the immunoglobulin heavy chain is set forth in SEQ ID NO.: 16.
4. The antibody agent of claim 2, n the immunoglobulin light chain is set forth in 25 SEQ ID NO.: 5 and the immunoglobulin heavy chain is set forth in SEQ ID NO.: 13.
5. The antibody agent of claim 2, wherein the immunoglobulin light chain is set forth in
SEQ ID NO.: 7 and the immunoglobulin heavy chain is set forth in SEQ ID NO.: 15. 30 6. The antibody agent of claim 2, n the immunoglobulin light chain is fused to a polypeptide set forth in SEQ ID NO.: 30 or SEQ ID NO.: 31.
7. The antibody agent of claim 1 or claim 2, conjugated to a therapeutic agent or detection agent.
8. The antibody agent of claim 7, wherein the antibody is conjugated to a radio-isotope, a drug agent, a nanoparticle, or an immune-toxin.
9. The antibody agent of claim 7, wherein the antibody is conjugated to a diagnostic or 5 g agent, or both.
10. The antibody agent of claim 1 or claim 2, wherein the antibody agent is a bispecific antibody having a first and a second specificity, and wherein the first specificity binds to protein 2Ig-B7H3 or 4Ig-B7H3, and the second icity binds to CD3 on T cells or 1,4,7,10- 10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
11. An scFv that binds specifically to protein 2Ig-B7H3 or 4Ig-B7H3 and ses the polypeptide set forth in a SEQ ID NO. selected from the group consisting of SEQ ID NO.: 24, 26 and 27.
12. The scFv of claim 11, wherein the polypeptide is fused to a second polypeptide set forth in SEQ ID NO.: 28 or SEQ ID NO.: 29.
13. The scFv of claim 11 or claim 12, wherein the scFv is conjugated to a therapeutic agent 20 or detection agent.
14. A pharmaceutical composition sing the antibody agent of any one of claims 1 to 10 or the scFv of any one of claims 11 to 13, and a pharmaceutically acceptable carrier. 25
15. Use of the antibody agent of any one of claims 1 to 10 or the scFv of any one of claims 11 to 13 in the manufacture of a ment for treating cancer in a t.
16. The use of claim 15, wherein the cancer is or comprises a neuroblastoma. 30
17. The use of claim 15, wherein the cancer is or comprises a cervical cancer.
18. The use of claim 15, wherein the cancer comprises B7H3-positive tumor cells.
19. Use of the antibody agent of any one of claims 1 to 10 or the scFv of any one of claims 35 11 to 13 in the manufacture of a medicament for ting the immune system in a patient.
20. Use of an antibody agent that binds to B7H3’s FG-loop in the manufacture of a medicament for enchancing T-cell mediated toxicity in a subject, wherein the antibody agent comprises: light chain CDR1, CDR2, and CDR3 as set forth in SEQ ID NOs: 34, 36, and 38, 5 respectively, and heavy chain CDR1, CDR2, and CDR3 as set forth in SEQ ID NOs: 58, 60, and 62, respectively.
21. The use of claim 20, wherein the antibody agent comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein said globulin heavy chain comprises 10 a sequence as set forth in SEQ ID NO: 13 or SEQ ID NO: 15, and said immunoglobulin light chain comprises a ce as set forth in SEQ ID NO: 5 or SEQ ID NO: 7.
22. A DNA or RNA encoding an antibody agent of any one of claims 1 to 10. 15
23. An isolated cell that expresses an antibody agent of any one of claims 1 to 10.
24. A method of preparing an isolated cell that ses an antibody agent, comprising transfecting or virally transducing a cell with the DNA of claim 22. 20
25. Use of the antibody agent of any one of claims 1 to 10 in the manufacture of a medicament for treating a patient by tmental radioimmunotherapy (cRIT).
26. The use of claim 25, wherein the medicament is to be administered intrathecally, intraperitoneally, or by convection enhanced delivery. SUBSTITUTE SHEET (RULE 26) HUMANIZATION BASED ON CDRGRAFTING AND U HOMOLOGYTO HUMAN TEMPLATES ch8H9AND hU8H9 H1L1, H1L2, H2L1, H2L2 IN SILICO SIMULATIONS OF 8H9 HOMOLOGY 3 MODEL STRUCTURE, TO R AFFINITY hu8H9 Q 3,1 IN SILICO SIMULATION YEAST DISPLAYAFFINITY MANUTRATION, 0F 8H9 CRYSTAL U TO ENHANCE ANTIGEN BINDING STRUCTURE, TO MAXIMIZE HUMAN Egg CONTENT SUBSTITUTE SHEET (RULE 26) STOP) SAMPLE START), SAMPLE 0 200 400 600 800 1000 1200 1400 1600 1800 TIME 3 SUBSTITUTE SHEET (RULE 26) B7H3 ELISA -o- ch8H9 -I:I- hu8H9 H1L1 -A— hu8H9 H1L2 —v— hu8H9 H2L1 -<>- hu8H9 H2L2 0.00001 0.0001 0.001 0.01 0.1 1 CONCENTRATION ) SUBSTITUTE SHEET (RULE 26) A B 4 1 3 0.8 $32 5%. 0-6 8 8 0.4 1 0.2 0 0 100 1000 10000 100000 0.01 0.1 1 10 DILUTION CONCENTRATION ) SUBSTITUTE SHEET (RULE 26) Egoga _ ., I-F4¢ «or no? Nor For 00? No? I-F4¢ w m N F o OOOOO x—x—x—x—x— H-ZTj gal-0.03% <1- C") N x—O 00000 «or H-ZTj gal-”Ea E.- me? \..“\\\\\-):-b~\“\\\\\ No? :44; <1- C") N‘— o gala-Ea 00000 x—x—x—x—x— <1- CV) N H-ZTj 00000 H'ZT? M we? EC: W\_n me? E No? IE Ea: E 58 E For E: mW 00? $8 E 205$ng Emor E For oer E :8 we? mor E For oer Fozaom Emmi NQZDOK 2%: ommmma SUBSTITUTE SHEET (RULE 26) 0.1pg/ml 1pg/ml § § 0 r 0 100 101 102 103104 Hu8H9H3L3scFv SUBSTITUTE SHEET (RULE 26) wwwwwwwwc?wwwwwwc?ww E—IE—IE—I OE—IE—IE—IE—IE—IE—IE—IE—IE—IE—IE—I ON ...................... >2: N ..xx.. ...x.. ...x.. ...... ...... ....x.. ..x.x.. ....... ....... ....... . .xxx.. .xxxx. :><°: :><: N :><: :><: >< N O N.OOOOO m.OmOOO 0.00000 m.OmOOO 0.00000 0.00000 0.00000 0.00000 OH.OOOOO OH.OOOOO OH.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO SUBSTITUTE SHEET (RULE 26) OO N >-I>-I>-I>-I>-I >-I>-I>-I>-I>-I>-I>-I>-I>-I>-I E—IE—IE—IE—IE—IE—IE—IE—IE—iE—IE—IEIEIE—IE—IE—IE—I OO 9522.200 Om .0_n_ OOO m.mmOmO N.OOOOO 0.00000 0.00000 0.00000 0.00000 0.00000 0.00000 0.00000 OH.OOOOO OH.OOOOO OH.OOOOO OO ON.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO ON.OOOOO SUBSTITUTE SHEET (RULE 26)
NZ729451A 2015-08-26 Antibodies, compositions, and uses NZ729451B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462042457P 2014-08-27 2014-08-27
PCT/US2015/047013 WO2016033225A2 (en) 2014-08-27 2015-08-26 Antibodies, compositions, and uses

Publications (2)

Publication Number Publication Date
NZ729451A NZ729451A (en) 2024-08-30
NZ729451B2 true NZ729451B2 (en) 2024-12-03

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