Claudin-6 antibodies and drug conjugates
The present disclosure provides antigen-binding proteins which bind to Claudin-6 (CLDN6). In various aspects, the antigen-binding proteins bind to Extracellular Loop 2 (EL2) of the extracellular domain of CLDN6. Related polypeptides, nucleic acids, vectors, host cells, and conjugates are further provided herein. Kits and pharmaceutical compositions comprising such entities are moreover provided. Also provided are methods of making an antigen-binding protein and methods of treating a subject having cancer.
1. An antigen-binding protein that binds to a human Claudin6 (CLDN6) protein (SEQ ID NO: 200) and comprises
(i) HC CDR1 comprising GFTFSNYW (SEQ ID NO: 23),
(ii) HC CDR2 comprising IRLKSDNYAT (SEQ ID NO: 24),
(iii) HC CDR3 comprising NDGPPSGX (SEQ ID NO: 457), wherein X at position 8 is selected from the group consisting of S, T, A, C, and Y;
(iv) LC CDR1 comprising ENIYSY (SEQ ID NO: 20),
(v) LC CDR2 comprising NAK (SEQ ID NO: 21), and
(vi) LC CDR3 comprising QHHYTVPWT (SEQ ID NO: 22).
2. The antigen-binding protein of claim 1 , wherein X is S whereby HC CDR3 comprises NDGPPSGS of SEQ ID NO: 457.
3. The antigen-binding protein of claim 1 , wherein X is T whereby HC CDR3 comprises NDGPPSGT of SEQ ID NO: 457.
4. The antigen-binding protein of claim 1 , wherein X is A whereby HC CDR3 comprises NDGPPSGA of SEQ ID NO: 457.
5. The antigen-binding protein of claim 1 , wherein X is C whereby HC CDR3 comprises NDGPPSGC of SEQ ID NO: 457.
6. The antigen-binding protein of claim 1 , wherein X is Y whereby HC CDR3 comprises NDGPPSGY of SEQ ID NO: 457.
7. The antigen-binding protein of claim 1 , wherein the antigen-binding protein is an antigen-binding antibody fragment.
8. The antigen-binding protein of claim 7 , wherein the antigen-binding antibody fragment is selected from the group consisting of scFv, F(ab′)2, Fab, Fab′, and Fv.
9. The antigen-binding protein of claim 1 , wherein the antigen-binding protein is an antibody.
10. The antigen-binding protein of claim 9 , wherein the antibody is a monoclonal antibody.
11. The antigen-binding protein of claim 9 , wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.
12. The antigen-binding protein of any one of claims 9-11 , wherein the antibody is an IgG.
13. The antigen-binding protein of claim 12 , wherein the IgG is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
14. The antigen-binding protein of claim 13 , wherein the IgG is IgG1.
15. A pharmaceutical composition comprising an antigen-binding protein that binds to a human Claudin6 (CLDN6) protein (SEQ ID NO: 200) and comprises:
(i) HC CDR1 comprising GFTFSNYW (SEQ ID NO: 23),
(ii) HC CDR2 comprising IRLKSDNYAT (SEQ ID NO: 24),
(iii) HC CDR3 comprising NDGPPSGX (SEQ ID NO: 457), wherein X at position 8 is selected from the group consisting of S, T, A, C, and Y;
(iv) LC CDR1 comprising ENIYSY (SEQ ID NO: 20),
(v) LC CDR2 comprising NAK (SEQ ID NO: 21), and
(vi) LC CDR3 comprising QHHYTVPWT (SEQ ID NO: 22),
and a pharmaceutically acceptable carrier, diluent, and/or excipient.
16. The pharmaceutical composition of claim 15 , wherein X is S whereby HC CDR3 comprises NDGPPSGS of SEQ ID NO: 457.
17. The pharmaceutical composition of claim 15 , wherein X is T whereby HC CDR3 comprises NDGPPSGT of SEQ ID NO: 457.
18. The pharmaceutical composition of claim 15 , wherein X is A whereby HC CDR3 comprises NDGPPSGA of SEQ ID NO: 457.
19. The pharmaceutical composition of claim 15 , wherein X is C whereby HC CDR3 comprises NDGPPSGC of SEQ ID NO: 457.
20. The pharmaceutical composition of claim 15 , wherein X is Y whereby HC CDR3 comprises NDGPPSGY of SEQ ID NO: 457.
21. The pharmaceutical composition of claim 15 , wherein the antigen-binding protein is an antigen-binding antibody fragment.
22. The pharmaceutical composition of claim 21 , wherein the antigen-binding antibody fragment is selected from the group consisting of scFv, F(ab′)2, Fab, Fab′, and Fv.
23. The pharmaceutical composition of claim 15 , wherein the antigen-binding protein is an antibody.
24. The pharmaceutical composition of claim 23 , wherein the antibody is a monoclonal antibody.
25. The pharmaceutical composition of claim 23 , wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.
26. The pharmaceutical composition of any one of claims 23-25 , wherein the antibody is an IgG.
27. The pharmaceutical composition of claim 26 , wherein the IgG is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
28. The pharmaceutical composition of claim 27 , wherein the IgG is IgG1.
29. The pharmaceutical composition of any one of claims 15 and 16-25 , further comprising a cytotoxic agent or a chemotherapeutic agent conjugated to the antigen-binding protein.
30. The pharmaceutical composition of claim 29 , further comprising a linker located between the antigen-binding protein and the cytotoxic or chemotherapeutic agent.
31. The conjugate of claim 30 , wherein the linker is a cleavable linker.
32. The pharmaceutical composition of claim 31 , wherein the cleavable linker comprises VC-PAB.
33. The pharmaceutical composition of claim 32 , wherein the cleavable linker comprises MC-VC-PAB.
34. The pharmaceutical composition of claim 29 , wherein the cytotoxic or chemotherapeutic agent is an anti-mitotic agent that inhibits cell division by blocking tubulin polymerization.
35. The pharmaceutical composition of claim 34 , wherein the anti-mitotic agent is an auristatin.
36. The pharmaceutical composition of claim 35 , wherein the auristatin is MMAE.
37. The pharmaceutical composition of claim 29 , wherein the antigen-binding protein is conjugated to MMAE via a cleavable linker comprising VC-PAB.
38. A conjugate comprising an antigen-binding protein that binds to a human Claudin6 (CLDN6) protein (SEQ ID NO: 200) and comprises:
(i) HC CDR1 comprising GFTFSNYW (SEQ ID NO: 23),
(ii) HC CDR2 comprising IRLKSDNYAT (SEQ ID NO: 24),
(iii) HC CDR3 comprising NDGPPSGX (SEQ ID NO: 457), wherein X at position 8 is selected from the group consisting of S, T, A, C, and Y;
(iv) LC CDR1 comprising ENIYSY (SEQ ID NO: 20),
(v) LC CDR2 comprising NAK (SEQ ID NO: 21), and
(vi) LC CDR3 comprising QHHYTVPWT (SEQ ID NO: 22),
wherein the antigen-binding protein is conjugated to a cytotoxic or chemotherapeutic agent.
39. The conjugate of claim 38 , wherein X is S whereby HC CDR3 comprises NDGPPSGS of SEQ ID NO: 457.
40. The conjugate of claim 39 , wherein the antigen-binding protein is conjugated to MMAE via a cleavable linker comprising MC-VC-PAB.
41. The conjugate of claim 38 , wherein X is T whereby HC CDR3 comprises NDGPPSGT of SEQ ID NO: 457.
42. The conjugate of claim 38 , wherein X is A whereby HC CDR3 comprises NDGPPSGA of SEQ ID NO: 457.
43. The conjugate of claim 38 , wherein X is C whereby HC CDR3 comprises NDGPPSGC of SEQ ID NO: 457.
44. The conjugate of claim 38 , wherein X is Y whereby HC CDR3 comprises NDGPPSGY of SEQ ID NO: 457.
45. The conjugate of claim 38 , wherein the antigen-binding protein is an antigen-binding antibody fragment.
46. The conjugate of claim 45 , wherein the antigen-binding antibody fragment is selected from the group consisting of scFv, F(ab′)2, Fab, Fab′, and Fv.
47. The conjugate of claim 38 , wherein the antigen-binding protein is an antibody.
48. The conjugate of claim 47 , wherein the antibody is a monoclonal antibody.
49. The conjugate of claim 47 , wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.
50. The conjugate of any one of claims 47-49 , wherein the antibody is an IgG.
51. The conjugate of claim 50 , wherein the IgG is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
52. The conjugate of claim 51 , wherein the IgG is IgG1.
53. The conjugate of claim 38 , further comprising a linker located between the antigen-binding protein and the cytotoxic or chemotherapeutic agent.
54. The conjugate of claim 53 , wherein the linker is a cleavable linker.
55. The conjugate of claim 54 , wherein the cleavable linker comprises an L-Valine-L-Citrulline-p-aminobenzyl group (VC-PAB).
56. The conjugate of claim 55 , wherein the cleavable linker comprises a maleimidocaproyl-L-Valine-L-Citrulline-p-aminobenzyl group (MC-VC-PAB).
57. The conjugate of claim 38 , wherein the cytotoxic or chemotherapeutic agent is an anti-mitotic agent that inhibits cell division by blocking tubulin polymerization.
58. The conjugate of claim 57 , wherein the anti-mitotic agent is an auristatin.
59. The conjugate of claim 58 , wherein the auristatin is monomethyl auristatin E (MMAE).