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NZ750420B2 - Antibody for anti-claudin 18a2 and use thereof - Google Patents
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NZ750420B2 - Antibody for anti-claudin 18a2 and use thereof - Google Patents

Antibody for anti-claudin 18a2 and use thereof

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Publication number
NZ750420B2
NZ750420B2 NZ750420A NZ75042017A NZ750420B2 NZ 750420 B2 NZ750420 B2 NZ 750420B2 NZ 750420 A NZ750420 A NZ 750420A NZ 75042017 A NZ75042017 A NZ 75042017A NZ 750420 B2 NZ750420 B2 NZ 750420B2
Authority
NZ
New Zealand
Prior art keywords
cell
seq
antibody
claudin
chimeric antigen
Prior art date
Application number
NZ750420A
Other versions
NZ750420A (en
Inventor
Hua Jiang
Zonghai Li
Zhimin Shi
Huamao Wang
Peng Wang
Linlin Yang
Original Assignee
Crage Medical Co Limited
Filing date
Publication date
Priority claimed from PCT/CN2017/082024 external-priority patent/WO2017186121A1/en
Application filed by Crage Medical Co Limited filed Critical Crage Medical Co Limited
Priority claimed from PCT/CN2017/092381 external-priority patent/WO2018006882A1/en
Publication of NZ750420A publication Critical patent/NZ750420A/en
Publication of NZ750420B2 publication Critical patent/NZ750420B2/en

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
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    • A61K47/6851—Medicinal 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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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    • C07K14/70517—CD8
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07K—PEPTIDES
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    • C—CHEMISTRY; METALLURGY
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    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
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    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
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    • C07K2319/00—Fusion polypeptide
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    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N2510/00—Genetically modified cells
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • G—PHYSICS
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    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
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    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N33/574—

Abstract

Provided in the present invention is an antibody for anti-claudin 18A2 and an immune effector cell targeting claudin 18A2. Also provided are methods for inducing cell death and treating tumours.

Claims (23)

Claims
1. An antibody ically binding to claudin 18A2, wherein the antibody is selected from the group consisting of: the CDR1, CDR2 and CDR3 s of the heavy chain variable region of the antibody are SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, and the CDR1, CDR2 and CDR3 regions of the light chain variable region of the antibody are SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54; or the CDR1, CDR2 and CDR3 regions of the heavy chain variable region of the antibody are SEQ ID NO: 49, SEQ ID NO 85, SEQ ID NO: 51, and the CDR1, CDR2 and CDR3 regions of the light chain le region of the antibody are SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54; or the antibody preferably is: an antibody having a heavy chain variable region of SEQ ID NO: 15 and a light chain variable region of SEQ ID NO: 13; an antibody having a heavy chain variable region of SEQ ID NO: 27 and a light chain le region of SEQ ID NO: 25; or an antibody having a heavy chain variable region of SEQ ID NO: 29 and a light chain variable region of SEQ ID NO: 25, an antibody having a heavy chain of SEQ ID NO: 63 and a light chain of SEQ ID NO: 65; or an antibody having a heavy chain of SEQ ID NO: 67 and a light chain of SEQ ID NO: 65.
2. The antibody of claim 1, n the antibody is a humanized antibody, a chimeric antibody or a fully humanized antibody; or the antibody is a monoclonal antibody; or the antibody is a single chain antibody or a domain antibody.
3. A chimeric antigen receptor, wherein the chimeric antigen receptor comprises following sequentially linked components: an antibody of claim 1 or 2, a transmembrane region and an intracellular signal region, wherein the intracellular signal region is preferably selected from the group ting of: an ellular signal region sequence of CD3?, FceRI?, CD27, CD28, CD137, 1005979175 CD134, MyD88, CD40, or a combination f; or the transmembrane region comprises a transmembrane region of CD8 or CD28, wherein the chimeric antigen receptor more preferably comprises sequentially linked an antibody, a embrane region and an intracellular signaling region as follows: the antibody of any one of claims 1-2, CD8 and CD3?; the antibody of any one of claims 1-2, CD8, CD137 and CD3?; or the antibody of any one of claims 1-2, a transmembrane region of CD28 molecule, an ellular signal region of CD28 molecule, and CD3?; or the dy of any one of claims 1-2, a transmembrane region of CD28 molecule, an intracellular signal region of CD28 molecule, CD137 and CD3?.
4. The chimeric antigen receptor of claim 3, wherein the chimeric antigen or comprises the amino acid sequence encoded by the nucleic acid sequence at positions 64- 1482 in SEQ ID NO: 90 or 91.
5. A multifunctional immunoconjugate comprising: an antibody of claim 1 or 2; and a functional molecule linked thereto, the functional molecule being selected from the group consisting of: a molecule targeting a surface marker on a tumor, a tumor-inhibiting molecule, a le targeting a surface marker of an immune cell or a detectable label, wherein the le ing a surface marker of an immune cell preferably is an antibody g to a T cell surface marker, which forms a bifunctional antibody with the antibody of claim 1 or 2 in which T cell is involved.
6. Use of the antibody of claim 1 or 2, the chimeric antigen receptor of claim 3 or 4, or the multifunctional immunoconjugate of claim 5 in the manufacture of a medicament for tumor inhibition, wherein the tumor is a tumor expressing claudin 18A2.
7. Use of the antibody of claim 1 or 2 or the multifunctional immunoconjugate of claim 5 preparing a reagent for diagnosing a tumor expressing claudin 18A2, the tumor expressing claudin 18A2 preferably for diagnosing a gastric cancer, pancreatic cancer, esophageal cancer, lung cancer; or 1005979175 preparing a chimeric antigen receptor modified immune cell; preferably, the immune cell includes: a T lymphocyte, NK cell or NKT lymphocyte.
8. A pharmaceutical composition sing the antibody of claim 1 or 2 or a nucleic acid encoding the antibody; or the immunoconjugate of claim 5 or a nucleic acid encoding the conjugate; or the chimeric antigen receptor of claim 3 or 4 or a nucleic acid encoding the chimeric antigen receptor; or an immune cell modified by the ic antigen receptor of claim 3 or 4.
9. A kit comprising: a container, and the pharmaceutical composition of claim 8 in the container; or a container, and the antibody of claim 1 or 2 or a c acid encoding the antibody in the container; or the immunoconjugate of claim 5 or a c acid encoding the conjugate; or the chimeric antigen receptor of claim 3 or 4 or a nucleic acid encoding the chimeric antigen or; or an immune cell modified by the chimeric antigen or of claim 3 or 4.
10. An antigen binding unit, n: the CDR1, CDR2 and CDR3 regions of the heavy chain variable region are SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, and the CDR1, CDR2 and CDR3 regions of the light chain variable region are SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54; or the CDR1, CDR2 and CDR3 regions of the heavy chain variable region are SEQ ID NO: 49, SEQ ID NO 85, SEQ ID NO: 51, and the CDR1, CDR2 and CDR3 regions of the light chain variable region are SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, and wherein: the antigen binding unit specifically binds to a claudin 18A2 peptide; and the antigen binding unit does not significantly bind to a claudin 18A1 peptide, or the n binding unit specifically binds to a claudin 18A2 peptide; and the antigen g unit, compared with a reference antigen binding unit, exhibits less non-specific binding to a claudin 18A1 peptide, wherein, optionally, 1005979175 (1) the reference antigen binding unit comprises a light chain amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 88 and/or a heavy chain amino acid sequence of SEQ ID NO: 87 or SEQ ID NO: 89; or (2) the claudin 18A2 peptide comprises an amino acid sequence of SEQ ID NO: 55; or (3) the claudin 18A1 peptide comprises an amino acid sequence of SEQ ID NO: 57; or (4) the non-specific binding of the antigen binding unit to the claudin 18A1 peptide does not exceed 20% of the specific g to the claudin 18A2 peptide; or (5) the g specificity is determined by flow cytometry, FACS, or ELISA; or (6) the antigen binding unit binds to the claudin 18A2 peptide with an EC50 of less than about 100 nM; or (7) the n binding unit is a monoclonal antibody, a zed antibody, a chimeric antibody, a multivalent antibody or a chimeric antigen receptor; or (8) the antigen g unit is scFv, Fv, Fab or (Fab)2.
11. A chimeric antigen receptor comprising an extracellular antigen binding unit, a embrane domain and an intracellular domain, wherein the extracellular antigen g unit comprises the antigen binding unit of claim 10.
12. A composition sing the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11, ally further comprising Type I eron.
13. A nucleic acid encoding the antibody of claim 1 or 2, the chimeric antigen receptor of claim 3 or 4, the multifunctional immunoconjugate of claim 5, or the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11, wherein the nucleic acid ng the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11 is an isolated nucleic acid and, optionally, further encodes a type I interferon.
14. A vector comprising encoding the antibody of claim 1 or 2 or the chimeric antigen receptor of claim 3 or 4, wherein the vector is an expression vector, or a nucleic acid of encoding the antigen binding unit of claim 10 or the chimeric n receptor of claim 11 and optionally a type I interferon.
15. A virus comprising the vector of claim 14 encoding the chimeric antigen receptor of claim 3 or 4. 1005979175
16. An isolated host cell comprising the expression vector encoding the dy of claim 1 or 2 or having the nucleic acid encoding the antibody of claim 1 or 2 integrated into its genome; or expressing the n binding unit of claim 10 or the chimeric antigen or of claim 11 and optionally a type I interferon, the host cell optionally being (i) an immune response cell, (ii) a T cell, natural killer cell, cytotoxic T lymphocyte, natural killer T cell, DNT cell, and/or regulatory T cell, (iii) an NK92 cell, (iv) a host cell being cytotoxic to a cell comprising a claudin 18A2 peptide and the claudin 18A2 peptide comprises the amino acid sequence of SEQ ID NO: 55, or (v) a host cell not having significant cytotoxicity to a cell comprising a claudin 18A1 peptide while not comprising a claudin 18A2 peptide, the claudin 18A1 peptide comprises an amino acid sequence of SEQ ID NO: 57, and the claudin 18A2 peptide comprises the amino acid ce of SEQ ID NO: 55; or comprising a nucleic acid encoding the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11 and optionally a type I interferon.
17. The host cell of claim 16, wherein the host cell ses a nucleic acid sequence of SEQ ID NO: 90 or 91 or the tide sequence comprising positions 64 to 1482 thereof.
18. A method for producing the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11 or the ition of claim 12, including: culturing the host cell of claim 16 or 17 expressing the antigen g unit of claim 10 or the chimeric antigen receptor of claim 11 and optionally a type I interferon, the host cell optionally being (i) an immune response cell, (ii) a T cell, natural killer cell, cytotoxic T cyte, natural killer T cell, DNT cell, and/or regulatory T cell, (iii) an NK92 cell, (iv) a host cell being cytotoxic to a cell comprising a claudin 18A2 peptide and the claudin 18A2 peptide comprises the amino acid sequence of SEQ ID NO: 55, or (v) a host cell not having significant cytotoxicity to a cell comprising a claudin 18A1 peptide while not comprising a claudin 18A2 peptide, the n 18A1 peptide comprises an amino acid sequence of SEQ ID NO: 57, and the claudin 18A2 peptide comprises the amino acid sequence of SEQ ID NO: 55, under suitable conditions, and obtaining the product expressed by the host cell.
19. Use of the antigen g unit of claim 10, the chimeric n receptor of claim 11, the composition of claim 12 or the host cell of claim 16 or 17 expressing the antigen 1005979175 binding unit of claim 10 or the chimeric n receptor of claim 11 and optionally a type I interferon in the manufacture of a medicament for inducing the death of a cell comprising a claudin 18A2 peptide, the host cell optionally being (i) an immune response cell, (ii) a T cell, natural killer cell, cytotoxic T lymphocyte, natural killer T cell, DNT cell, and/or regulatory T cell, (iii) an NK92 cell, (iv) a host cell being xic to a cell sing a n 18A2 peptide and the claudin 18A2 peptide comprises the amino acid sequence of SEQ ID NO: 55, or (v) a host cell not having significant cytotoxicity to a cell comprising a claudin 18A1 peptide while not comprising a claudin 18A2 peptide, the claudin 18A1 peptide comprises an amino acid sequence of SEQ ID NO: 57, and the claudin 18A2 peptide ses the amino acid sequence of SEQ ID NO: 55, wherein the cell is preferably contacted with the antigen binding unit, the chimeric antigen receptor, the composition or host cell in vitro or in vivo, wherein the cell is optionally a cancer cell, a solid tumor cell, or is selected from the group consisting of: a gastric cancer cell, esophageal cancer cell, intestinal cancer cell, pancreatic cancer cell, nephroblastoma cell, lung cancer cell, n cancer cell, colon cancer cell, rectal cancer cell, liver cancer cell, head and neck cancer cell, chronic myeloid leukemia cell and gallbladder cancer cell.
20. Use of the antigen binding unit of claim 10, the chimeric antigen receptor of claim 11, the composition of claim 12, the vector of claim 14 comprising a nucleic acid of encoding the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11 and optionally a type I eron and / or the host cell of claim 16 or 17 expressing the antigen binding unit of claim 10 or the chimeric antigen receptor of claim 11, in the manufacture of a medicament for treating a tumor in an individual in need thereof; wherein the ment is optionally for administration with, or formulated with, a type I interferon, wherein preferably the tumor is a solid tumor, or is gastric cancer, esophageal cancer, intestinal cancer, pancreatic cancer, nephroblastoma, lung cancer, ovarian cancer, colon cancer, rectal cancer, liver cancer, head and neck , chronic myelogenous ia or gallbladder cancer; wherein the medicament optionally further includes an additional therapeutic agent, wherein the onal therapeutic agent is ally at least one selected from the group consisting of icin, oxaliplatin and 5-fluorouracil. 1005979175
21. Use of the chimeric antigen receptor of claim 3 or 4, the nucleic acid of claim 13 encoding it, the expression vector of claim 14 comprising the nucleic acid, or the virus of claim 15 for preparing chimeric antigen or-modified immune cells targeting tumor cells expressing claudin 18A2, wherein the tumor expressing claudin 18A2 preferably includes: gastric cancer, pancreatic cancer, esophageal cancer, lung cancer.
22. An isolated chimeric antigen receptor-modified immune cell transduced with the nucleic acid of claim 13 encoding the ic antigen receptor of claim 3 or 4, the expression vector of claim 14 comprising said nucleic acid or the virus of claim 15; or having the chimeric antigen receptor of claim 3 or 4 expressed on the e; the immune cell preferably being a T lymphocyte, NK cell or NKT lymphocyte and optionally further ng an encoding ce for an exogenous cytokine; or further expressing another chimeric antigen receptor which does not contain CD3? but contains an intracellular signal domain of CD28, an intracellular signal domain of CD137, or a combination of the both; or further expressing a chemokine or; preferably, said chemokine receptor comprises: CCR); or further sing an siRNA which can reduce expression of PD-1 or a protein which can block PD-L1; or endogenous PD-1 in the immune cell is knocked out by gene editing techniques; or further expressing a safety switch.
23. Use of the chimeric antigen receptor-modified immune cell of claim 22 in the manufacture of a medicament for tumor inhibition, wherein the tumor is a tumor sing n 18A2; the tumor preferably including gastric cancer, pancreatic cancer, esophageal cancer, lung cancer.
NZ750420A 2017-07-10 Antibody for anti-claudin 18a2 and use thereof NZ750420B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201610536449 2016-07-08
PCT/CN2017/082024 WO2017186121A1 (en) 2016-04-26 2017-04-26 Method for improving function of immune response cell
PCT/CN2017/092381 WO2018006882A1 (en) 2016-07-08 2017-07-10 Antibody for anti-claudin 18a2 and use thereof

Publications (2)

Publication Number Publication Date
NZ750420A NZ750420A (en) 2025-06-27
NZ750420B2 true NZ750420B2 (en) 2025-09-30

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