Anti-Claudin 18.2 antibody and application thereof

Patent metadata

Field	Value
Publication number	US-12428478-B2
Application number	US-202017442939-A
Country	US
Kind code	B2
Filing date	Mar 31, 2020
Priority date	Apr 1, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

The present disclosure relates to an anti-Claudin 18.2 antibody and an application thereof. Specifically, the present invention relates to an anti-Claudin 18.2 antibody; a mouse-derived antibody, chimeric antibody, humanized antibody and antigen-binding fragment thereof which contain a CDR of the anti-Claudin 18.2 antibody, and a use thereof as a medicine. In particular, the present disclosure relates to a use of the anti-Claudin 18.2 antibody in the preparation of a drug for treating Claudin 18.2 positive diseases or disorders.

First claim

What is claimed is:

1. An anti-Claudin 18.2 antibody comprising a heavy chain variable region and a light chain variable region, wherein:
i) the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, respectively, and
the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively; or
ii) the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11, respectively, and
the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively.

2. The anti-Claudin 18.2 antibody according to claim 1 , wherein the antibody is a murine antibody, a chimeric antibody, or a humanized antibody.

3. The anti-Claudin 18.2 antibody according to claim 1 , comprising a heavy chain variable region and a light chain variable region, wherein:
1) The amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 3 or has at least 90% identity to SEQ ID NO: 3, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 4 or has at least 90% identity to SEQ ID NO: 4;
2) The amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 24 or has at least 90% identity to SEQ ID NO: 24, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 21 or has at least 90% identity to SEQ ID NO: 21;
3) The amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 5 or has at least 90% identity to SEQ ID NO: 5, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 6 or has at least 90% identity to SEQ ID NO: 6; or
4) The amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 31 or has at least 90% identity to SEQ ID NO: 31, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 28 or has at least 90% identity to SEQ ID NO: 28.

4. The anti-Claudin 18.2 antibody according to claim 3 , wherein the antibody is a humanized antibody comprising a framework region derived from a human antibody or a framework region variant thereof, and the framework region variant has 1 to 10 back mutation(s) on the human antibody light chain framework region and/or the heavy chain framework region;
wherein the framework region variant comprises mutation(s) selected from a) or b) below:
a) one or more back mutation(s) selected from the group consisting of 22S, 85I and 87H comprised in the light chain variable region, and/or one or more back mutation(s) selected from the group consisting of 48I, 82T and 69M comprised in the heavy chain variable region; or
b) one or more back mutation(s) selected from the group consisting of 4L and 22S comprised in the light chain variable region, and/or one or more back mutation(s) selected from the group consisting of 38K, 40R, 48I, 66K, 67A, 69L, 71L and 73K comprised in the heavy chain variable region.

5. The anti-Claudin 18.2 antibody according to claim 2 , wherein the antibody comprises a heavy chain variable region and a light chain variable region as shown below:
i) the heavy chain variable region sequence as shown in SEQ ID NO: 3 and the light chain variable region sequence as shown in SEQ ID NO: 4; or
ii) the heavy chain variable region sequence as shown in SEQ ID NO: 24, 25, 26 or 27 and the light chain variable region sequence as shown in SEQ ID NO: 21, 22 or 23; or
iii) the heavy chain variable region sequence as shown in SEQ ID NO: 5 and the light chain variable region sequence as shown in SEQ ID NO: 6; or
iv) the heavy chain variable region sequence as shown in SEQ ID NO: 31, 32, 33 or 34 and the light chain variable region sequence as shown in SEQ ID NO: 28, 29 or 30.

6. The anti-Claudin 18.2 antibody according to claim 1 , wherein the antibody further comprises a heavy chain constant region and a light chain constant region;
wherein the heavy chain constant region is selected from the group consisting of human IgG1, IgG2, IgG3 and IgG4 constant region(s) and variant(s) thereof,
and the light chain constant region is selected from the group consisting of human antibody κ and λ chain constant region(s) and variant(s) thereof.

7. The anti-Claudin 18.2 antibody according to claim 1 , comprising:
c) a heavy chain as shown in SEQ ID NO: 35 and a light chain as shown in SEQ ID NO: 36;
d) a heavy chain as shown in SEQ ID NO: 42, 43, 44 or 45 and a light chain as shown in SEQ ID NO: 39, 40 or 41;
e) a heavy chain as shown in SEQ ID NO: 37 and a light chain as shown in SEQ ID NO: 38; or
f) a heavy chain as shown in SEQ ID NO: 49, 50, 51 or 52 and a light chain as shown in SEQ ID NO: 46, 47 or 48.

8. The anti-Claudin 18.2 antibody according to claim 1 , comprising:
a heavy chain as shown in SEQ ID NO: 44 and a light chain as shown in SEQ ID NO: 41; or
a heavy chain as shown in SEQ ID NO: 49 and a light chain as shown in SEQ ID NO: 47.

9. A nucleic acid molecule encoding the anti-Claudin 18.2 antibody of claim 1 .

10. A host cell comprising the nucleic acid molecule of claim 9 .

11. An antibody-drug conjugate comprising the anti-Claudin 18.2 antibody according to claim 1 and a cytotoxic drug.

12. A pharmaceutical composition, comprising a therapeutically effective amount of the anti-Claudin 18.2 antibody according to claim 1 and one or more pharmaceutically acceptable carriers, diluents, buffers or excipients.

13. A method for the treatment of a disease associated with Claudin 18.2, the method including administering to a subject a therapeutically effective amount of the anti-Claudin 18.2 antibody of claim 1 ; wherein the disease is a tumor.

14. The method of claim 13 , wherein the disease is selected from the group consisting of: head and neck squamous cell cancer, head and neck cancer, brain cancer, glioma, glioblastoma multiforme, neuroblastoma, central nervous system cancer, neuroendocrine tumor, laryngopharyngeal carcinoma, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatocellular tumor, hepatocellular carcinoma, liver and gallbladder cancer, pancreatic cancer, gastric cancer, gastrointestinal cancer, intestinal cancer, colon cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, melanoma, leukemia, lymphoma, bone cancer, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, Krukenberg tumor, myeloproliferative tumor, squamous cell carcer, Ewing sarcoma, systemic light chain amyloidosis and Merkel cell cancer.

15. The anti-Claudin 18.2 antibody according to claim 4 , wherein the framework region variant comprises mutation(s) selected from a-1) or b-1) below:
a-1) amino acid back mutations 22S, 85I and 87H comprised in the light chain variable region, and back mutations 48I and 82T comprised in the heavy chain variable region; or
b-1) back mutation 4L comprised in the light chain variable region;

back mutation 82T comprised in the heavy chain variable region, wherein “82” indicates position 82A according to Kabat Criteria.

16. The anti-Claudin 18.2 antibody according to claim 5 , wherein the anti-Claudin 18.2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region as shown below:
i) the heavy chain varia

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Yang Yang
• Ge Hu
• Tao Weikang

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title