Anti-AVB6 antibodies and antibody-drug conjugates

Patent metadata

Field	Value
Publication number	US-11827709-B2
Application number	US-202017112533-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Dec 5, 2019
Publication date	Nov 28, 2023
Grant date	Nov 28, 2023

Abstract

Provided are novel anti-αvβ6 antibodies and antibody-drug conjugates and methods of using such anti-αvβ6 antibodies and antibody-drug conjugates to treat cancer.

First claim

The invention claimed is:

1. An isolated anti-αvβ6 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:
(i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:31;
(ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:32; and
(iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33; and

wherein the light chain variable region comprises:
(i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:37;
(ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:42; and
(iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:39

wherein the CDRs are determined by Kabat.

2. An isolated anti-αvβ6 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises:
(i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:34;
(ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:35; and
(iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:36; and

wherein the light chain variable region comprises:
(i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:43;
(ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:44; and
(iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:45

wherein the CDRs are determined by IMGT.

3. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the antibody is humanized.

4. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 6 and the light chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 17.

5. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6 and the light chain variable region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17.

6. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 6 and the light chain variable region comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 17.

7. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 6 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:17.

8. The antibody or antigen-binding fragment of claim 3 , wherein H2 is occupied by F, H28 is occupied by S, H48 is occupied by I, H67 is occupied by A, H69 is occupied by L, H71 is occupied by V, H73 is occupied by K, H78 is occupied by A, H93 is occupied by T, L69 is occupied by R, and L71 is occupied by Y, and wherein the numbering is via the Kabat numbering system.

9. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the antibody or antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence comprising SEQ ID NO:21 and the light chain has an amino acid sequence comprising SEQ ID NO:29.

10. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the antibody or antigen-binding fragment is an antigen-binding fragment, and wherein the antigen-binding fragment is selected from the group consisting of Fab, Fab′, F(ab′) 2 , Fab′-SH, Fv, diabody, linear antibody, and single-chain antibody fragment.

11. The antibody or antigen-binding fragment of claim 1 or claim 2 , wherein the heavy chain variable region of the antibody is fused to a heavy chain constant region and the light chain variable region is fused to a light chain constant region.

12. The antibody or antigen-binding fragment of claim 11 , wherein the heavy chain constant region is of the IgG1 isotype.

13. An antibody-drug conjugate comprising the antibody or antigen-binding fragment of claim 1 or claim 2 conjugated to a cytotoxic or cytostatic agent.

14. The antibody-drug conjugate of claim 13 , wherein the antibody or antigen-binding fragment is conjugated to the cytotoxic or cytostatic agent via a linker.

15. The antibody-drug conjugate of claim 13 , wherein the cytotoxic or cytostatic agent is a monomethyl auristatin.

16. The antibody-drug conjugate of claim 15 , wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).

17. The antibody-drug conjugate of claim 16 , wherein the antibody or antigen binding fragment thereof is conjugated to MMAE via an enzyme-cleavable linker unit.

18. The antibody-drug conjugate of claim 17 , wherein the enzyme-cleavable linker unit comprises a Val-Cit linker.

19. The antibody-drug conjugate of claim 18 , wherein the antibody or antigen binding fragment thereof is conjugated to MMAE via a linker unit that has the formula: -A a -W w —Y y —; wherein -A- is a stretcher unit, a is 0 or 1; —W— is an amino acid unit, w is an integer ranging from 0 to 12; and —Y— is a spacer unit, y is 0, 1, or 2.

20. The antibody-drug conjugate of claim 19 , wherein the stretcher unit has the structure of Formula I below; wherein the amino acid unit is Val-Cit; and wherein the spacer unit is a p-aminobenzyl alcohol (PAB) group having the structure of Formula II below;

21. The antibody-drug conjugate of claim 14 , wherein the linker is attached to monomethyl auristatin E and has the structure:

wherein Ab is the antibody or antigen-binding fragment and p denotes a number from 1 to 16.

22. The antibody-drug conjugate of claim 21 , wherein the average value of p in a population of the antibody-drug conjugate is about 4.

23. A method of treating cancer in a subject, the method comprising administering to the subject the antibody-drug conjugate of claim 13 .

24. The method of claim 23 , wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck cancer, esophageal cancer, breast cancer, ovarian cancer, bladder cancer, skin cancer (SCC), ovarian cancer, cervical cancer, gastric cancer, and pancreatic cancer.

25. The method of claim 23 , wherein the cancer is non-small cell lung cancer.

26. The method of claim 23 , wherein the cancer is head and neck cancer.

27. The method of claim 23 , wherein the antibody or antigen-binding fragment or antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

28. The method of claim 23 , wherein the subject is a human.

29. A pharmaceutical composition comprising the antibody-drug conjugate of claim 13 and one or more agents selected from the group consisting of a physiologically acceptable carrier,

Assignees

• Seagen Inc

Inventors

• Ryan Maureen
• Westendorf Lori
• Meyer Eric Bradley
• Kostner Heather Jean

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K47/68031 Primary

  the drug being an auristatin · CPC title

• C07K16/2839 Primary

  against the integrin superfamily · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title