Antibody against claudin 18A2 and use thereof
Provided are an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, a derivative comprising said antibody or antigen-binding fragment thereof, a pharmaceutical composition, and related use of said antibody or antigen-binding fragment thereof for treating, diagnosing and detecting cancers.
1. An anti-CLDN18.2 antibody or antigen-binding fragment thereof,
comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an HCDR1, an HCDR2, and an HCDR3 and the light chain variable region comprising an LCDR1, an LCDR2, and an LCDR3 selected from the group consisting of:
(1) SEQ ID NOs: 37, 38, 39, 86, 93, 97;
(2) SEQ ID NOs: 40, 41, 42, 87, 94, 98;
(3) SEQ ID NOs: 43, 41, 44, 88, 93, 99;
(4) SEQ ID NOs: 45, 46, 47, 87, 95, 100;
(5) SEQ ID NOs: 37, 48, 39, 88, 93, 97;
(6) SEQ ID NOs: 49, 50, 51, 88, 93, 101;
(7) SEQ ID NOs: 49, 52, 51, 89, 93, 102;
(8) SEQ ID NOs: 53, 54, 55, 88, 93, 100;
(9) SEQ ID NOs: 56, 57, 58, 90, 93, 103;
(10) SEQ ID NOs: 59, 60, 61, 91, 96, 104;
(11) SEQ ID NOs: 62, 63, 64, 88, 93, 98;
(12) SEQ ID NOs: 65, 66, 67, 92, 93, 105;
(13) SEQ ID NOs: 68, 69, 70, 88, 93, 106;
(14) SEQ ID NOs: 71, 72, 73, 88, 93, 107;
(15) SEQ ID NOs: 74, 75, 76, 88, 93, 106;
(16) SEQ ID NOs: 77, 78, 79, 87, 93, 108;
(17) SEQ ID NOs: 80, 81, 82, 88, 93, 109;
(18) SEQ ID NOs: 83, 84, 85, 88, 93, 110;
(19) SEQ ID NOs: 71, 72, 73, 112, 93, 107;
(20) SEQ ID NOs: 71, 72, 73, 113, 93, 107;
(21) SEQ ID NOs: 83, 84, 85, 111, 93, 110;
(22) SEQ ID NOs: 83, 84, 85, 112, 93, 110; and
(23) SEQ ID NOs: 83, 84, 85, 113, 93, 110;
wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are arranged in the order of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 in each group.
2. The anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , comprising at least 80% to 100% sequence identity to a heavy chain variable region and a light chain variable region of any one of the groups consisting of:
(1) SEQ ID NOs: 1 and 2;
(2) SEQ ID NOs: 3 and 4;
(3) SEQ ID NOs: 5 and 6;
(4) SEQ ID NOs: 7 and 8;
(5) SEQ ID NOs: 9 and 10;
(6) SEQ ID NOs: 11 and 12;
(7) SEQ ID NOs: 13 and 14;
(8) SEQ ID NOs: 15 and 16;
(9) SEQ ID NOs: 17 and 18;
(10) SEQ ID NOs: 19 and 20;
(11) SEQ ID NOs: 21 and 22;
(12) SEQ ID NOs: 23 and 24;
(13) SEQ ID NOs: 25 and 26;
(14) SEQ ID NOs: 27 and 28;
(15) SEQ ID NOs: 29 and 30;
(16) SEQ ID NOs: 31 and 32;
(17) SEQ ID NOs: 33 and 34;
(18) SEQ ID NOs: 35 and 36;
(19) SEQ ID NOs: 27 and 115;
(20) SEQ ID NOs: 27 and 116;
(21) SEQ ID NOs: 35 and 117;
(22) SEQ ID NOs: 35 and 118;
(23) SEQ ID NOs: 35 and 119;
(24) SEQ ID NOs: 120 and 121;
(25) SEQ ID NOs: 120 and 123;
(26) SEQ ID NOs: 120 and 124;
(27) SEQ ID NOs: 122 and 121;
(28) SEQ ID NOs: 125 and 126;
(29) SEQ ID NOs: 125 and 127; and
(30) SEQ ID NOs: 128 and 126.
3. The anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , which is a murine antibody, a chimeric antibody, or a humanized antibody.
4. The anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , further comprising a heavy chain constant region and/or light chain constant region, optionally wherein the heavy chain constant region comprises an FC or a variant Fc.
5. A conjugate formed by coupling the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 to a capture label or a detection label, the detection label comprising radionuclides, luminescent substances, colored substances, or enzymes.
6. A multispecific antibody, wherein one antigen-binding
domain comprises the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 .
7. The multispecific antibody of claim 6 , which is a bispecific antibody.
8. An antibody-drug conjugate, comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , the antibody-drug conjugate being formed by antibody-linker-toxin interconnections.
9. A chimeric antigen receptor, comprising an extracellular recognition unit comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 .
10. A nucleic acid encoding the anti-CLDN18.2 antibody or antigen binding fragment thereof claim 1 .
11. A recombinant vector comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 .
12. A host cell comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 being integrated into the genome or comprising a recombinant vector comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 .
13. A method of preparing the anti-CLDN18.2 antibody or antigen binding fragment thereof of claim 1 , comprising: culturing one or more host cells comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof according to claim 1 , or culturing one or more host cells comprising a recombinant vector comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof according to claim 1 under suitable conditions and purifying the expression products from the cells.
14. A pharmaceutical composition comprising an effective amount of the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , or comprising an effective amount of a multispecific or bispecific antibody wherein one antigen-binding domain of the multispecific or bispecific antibody comprises the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , or comprising an effective amount of an antibody-drug conjugate comprising the anti-CLDN18.2 antibody or antigen binding fragment thereof of claim 1 , or comprising an effective amount of a chimeric antigen receptor comprising an extracellular recognition unit comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , or comprising an effective amount of a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof of claim 1 , or comprising an effective amount of a recombinant vector comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof according to claim 1 , or comprising an effective amount of a host cell comprising a recombinant vector comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof according to claim 1 , or comprising an effective amount of a host cell comprising a nucleic acid encoding the anti-CLDN18.2 antibody or antigen-binding fragment thereof according to claim 1 being integrated into the genome the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or one or more additional therapeutic agents.
15. A method of inducing cell death of CLDN18.2-expressing cells, comprising contacting the cells with the pharmaceutical composition of claim 14 .
16. A method of treating a disease associated with expression of CLDN18.2 in a subject, comprising administering to a subject in need thereof the pharmaceutical composition of claim 14 , optionally wherein the method further comprises administering to the subject in need an additional therapeutic agent.
17. The method of claim 16 , wherein the disease is a tumor; and wherein the additional therapeutic agent comprises one or more selected from the group consisting of: chemotherapeutic agents, cytotoxic agents, radiotherapeutic agents, cancer vaccines, anti-neoplastic agents, targeted anti-cancer agents, anti-angiogenic agents, biological response modifiers, cytokines, hormones, anti-metastatic agents, immunotherapeutic agents, oncolytic viruses, and protease inhibitors.
18. The method of claim 16 , wherein the disease is gastric cancer, esophageal cancer, intestinal cancer, pancreatic cancer, nephroblastoma, lung cancer, ovarian cancer, colon cancer, rectal cancer, liver cancer, head and neck cancer, chronic myelogenous leukemia, or gallbladder cancer.