Method for treating cancer with c-kit antibodies
Disclosed herein are antibody molecules binding specifically to C-KIT, antigen-binding portions thereof and medical uses therefor.
1. A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-C-KIT antibody or an antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein
(a) the VH region amino acid sequence comprises HCDR1 of GYTFTDYYMN (SEQ ID NO: 13), HCDR2 of MGRIYPGSGNTYYAQKFQG (SEQ ID NO: 14) and HCDR3 of GVYYYDY (SEQ ID NO: 15); and the VL region amino acid sequence comprises LCDR1 of RASQGIRTNLA (SEQ ID NO: 16), LCDR2 of AASSLQS (SEQ ID NO: 24) and LCDR3 of QQYNSYPRT (SEQ ID NO: 12); or
(b) the VH region amino acid sequence comprises HCDR1 of GYTFTDYYMN (SEQ ID NO: 13), HCDR2 of MGRIYPGSGNTYYAQKFQG (SEQ ID NO: 14) and HCDR3 of GVYYYDY (SEQ ID NO: 15); and the VL region amino acid sequence comprises LCDR1 of RASQGIRTNLA (SEQ ID NO: 16), LCDR2 of AASSLQS (SEQ ID NO: 24) and LCDR3 of QQYANYPRT (SEQ ID NO: 25); and
wherein the cancer is gastrointestinal stromal cancer (GIST), lung cancer, acute myeloid leukemia (AML) or a mast cell tumor.
2. The method of claim 1 , wherein
(a) the VH region amino acid sequence comprises SEQ ID NO:185 and the VL region amino acid sequence comprises SEQ ID NO:186; or
(b) the VH region amino acid sequence comprises SEQ ID NO:187 and the VL region amino acid sequence comprises SEQ ID NO:188.
3. The method of claim 1 , wherein the antibody is humanized or chimeric.
4. The method of claim 1 , wherein the VH region, the VL region, or both the VH and the VL region comprise one or more human framework region amino acid sequences.
5. The method of claim 1 , wherein the VH region, the VL region, or both the VH and the VL region comprise a human variable region framework scaffold amino acid sequence into which the CDRs have been inserted.
6. The method of claim 1 , wherein the VH region comprises an IGHV1-46 human germline scaffold amino acid sequence into which the HCDR1, HCDR2 and HCDR3 amino acid sequences have been inserted.
7. The method of claim 1 , wherein the VL region comprises an IGKV1-16 human germline scaffold amino acid sequence into which the LCDR1, LCDR2 and LCDR3 amino acid sequences have been inserted.
8. The method of claim 1 , wherein the antibody comprises an immunoglobulin constant region.
9. The method of claim 8 , wherein the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY.
10. The method of claim 9 , wherein the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2.
11. The method of claim 8 , wherein the immunoglobulin constant region is immunologically inert.
12. The method of claim 9 , wherein the immunoglobulin constant region is a wild-type human IgG1 constant region, a human IgG1 constant region comprising the amino acid substitutions L234A, L235A and G237A or a human IgG1 constant region comprising the amino acid substitutions L234A, L235A, G237A and P331S.
13. The method of claim 9 , wherein the immunoglobulin constant region comprises SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201 or SEQ ID NO:202.
14. The method of claim 1 , wherein the antibody or antigen-binding portion is an Fab, an Fab′, an F(ab′)2, an Fv, an scFv, a maxibody, a minibody, a diabody, a triabody, a tetrabody, or a bis-scFv.
15. The method of claim 1 , wherein the antibody is monoclonal.
16. The method of claim 1 , wherein the antibody or antigen-binding portion binds specifically to (a) human C-KIT or (b) human C-KIT and cynomolgus C-KIT.
17. The method of claim 1 , wherein the antibody or antigen-binding portion is linked to a therapeutic agent.
18. The method of claim 17 , wherein the therapeutic agent is a cytotoxin, a radioisotope, a chemotherapeutic agent, an immunomodulatory agent, a cytostatic enzyme, a cytolytic enzyme, a therapeutic nucleic acid, an anti-angiogenic agent, an anti-proliferative agent, or a pro-apoptotic agent.
19. The method of claim 1 , wherein the antibody or antigen-binding portion is administered to the subject in the form of a pharmaceutical composition comprising the antibody or antigen-binding portion and a pharmaceutically acceptable carrier, diluent or excipient.
20. The method of claim 1 , wherein the antibody or antigen-binding portion is administered to the subject in a combination with an additional therapeutic agent.
21. The method of claim 20 , wherein the additional therapeutic agent is an anti-cancer agent.