Anti-kit antibodies
Provided herein, in one aspect, are antibodies that immunospecifically bind to a human KIT antigen comprising the fourth and/or fifth extracellular Ig-like domains (that is, D4 and/or D5 domains), polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. The antibodies can inhibit KIT activity, such as ligand-induced receptor phosphorylation. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to a KIT antigen, as well as methods of treating or managing a KIT-mediated disorder or disease and methods of diagnosing a KIT-mediated disorder or disease using the antibodies described herein.
1. An isolated antibody or an antigen-binding fragment thereof, which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15), comprising:
(i) a variable light (“VL”) chain region comprising a VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22, respectively; and
(ii) a variable heavy (“VH”) chain region comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25, respectively.
2. The antibody or antigen-binding fragment thereof of claim 1 , which immunospecifically binds to a D4/D5 region of human KIT (SEQ ID NO: 15), comprising:
(A) a VL chain region comprising the amino acid sequence of SEQ ID NO: 2, and a VH chain region comprising the amino acid sequence of SEQ ID NO: 3; or
(B) a VL chain region comprising the amino acid sequence of SEQ ID NO: 2 and a VH chain region comprising the amino acid sequence of SEQ ID NO: 5.
3. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a humanized monoclonal antibody.
4. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a monoclonal antibody.
5. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises an Fc region of a human IgG1 or IgG4 antibody.
6. The antibody or antigen-binding fragment of claim 1 , which is linked to an agent.
7. The antibody or antigen-binding fragment of claim 6 , wherein the agent is a toxin.
8. The antibody or antigen-binding fragment of claim 7 , wherein the toxin is abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin.
9. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 6 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
11. A kit comprising a container comprising the antibody or antigen-binding fragment thereof of claim 1 .
12. A kit comprising a container comprising the antibody or antigen-binding fragment of claim 6 .
13. The antibody or antigen-binding fragment of claim 1 , which further comprises a human heavy chain constant region.
14. The antibody or antigen-binding fragment of claim 13 , wherein the human heavy chain constant region is an IgG1 human heavy chain constant region.
15. The antibody or antigen-binding fragment of claim 1 , which further comprises a human light chain constant region.
16. The antibody or antigen-binding fragment of claim 13 , which further comprises a human light chain constant region.
17. The antibody or antigen-binding fragment of claim 15 , wherein the human light chain constant region is a human kappa light chain constant region.
18. The antibody or antigen-binding fragment of claim 16 , wherein the human light chain constant region is a human kappa light chain constant region.
19. The antibody or antigen-binding fragment of claim 14 , which further comprises a human light chain constant region.
20. The antibody or antigen-binding fragment of claim 19 , wherein the human light chain constant region is a human kappa light chain constant region.
21. The antibody or antigen-binding fragment of claim 1 , which further comprises a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 12 and a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 13.
22. The antibody or antigen-binding fragment of claim 16 , which is a humanized antibody.
23. The antibody or antigen-binding fragment of claim 20 , which is a humanized antibody.
24. The antibody or antigen-binding fragment of claim 6 , wherein the antibody or antigen-binding fragment thereof further comprises a human heavy chain constant region.
25. The antibody or antigen-binding fragment of claim 24 , wherein the human heavy chain constant region is an IgG1 human heavy chain constant region.
26. The antibody or antigen-binding fragment of claim 6 , wherein the antibody or antigen-binding fragment thereof further comprises a human light chain constant region.
27. The antibody or antigen-binding fragment of claim 24 , wherein the antibody or antigen-binding fragment thereof further comprises a human light chain constant region.
28. The antibody or antigen-binding fragment of claim 25 , wherein the antibody or antigen-binding fragment thereof further comprises a human light chain constant region.
29. The antibody or antigen-binding fragment of claim 26 , wherein the human light chain constant region is a human kappa light chain constant region.
30. The antibody or antigen-binding fragment of claim 27 , wherein the human light chain constant region is a human kappa light chain constant region.
31. The antibody or antigen-binding fragment of claim 28 , wherein the human light chain constant region is a human kappa light chain constant region.
32. The antibody or antigen-binding fragment of claim 6 , wherein the antibody or antigen-binding fragment thereof is a humanized monoclonal antibody.
33. The antibody or antigen-binding fragment of claim 27 , wherein the antibody or antigen-binding fragment thereof is a humanized monoclonal antibody.
34. The antibody or antigen-binding fragment of claim 31 , wherein the antibody or antigen-binding fragment thereof is a humanized monoclonal antibody.
35. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 3 and a pharmaceutically acceptable carrier.
36. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 22 and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 23 and a pharmaceutically acceptable carrier.
38. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 32 and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 34 and a pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 9 , which is in the form of a lyophilized formulation or aqueous solution.
41. The pharmaceutical composition of claim 10 , which is in the form of a lyophilized formulation or aqueous solution.