C-KIT antibodies and method for treating cancer with such
Disclosed herein are antibody molecules binding specifically to C-KIT, antigen-binding portions thereof and medical uses therefor.
1. An anti-C-KIT antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion 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 RASQGIRINLA (SEQ ID NO: 16), LCDR2 of SASSLQS (SEQ ID NO: 17) and LCDR3 of QQYANYPRT (SEQ ID NO: 25);
(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 SASSLQS (SEQ ID NO: 17) and LCDR3 of QQYNSYPRT (SEQ ID NO: 12);
(c) the VH region amino acid sequence comprises HCDR1 of GYTFTDYYMN (SEQ ID NO: 13), HCDR2 of MGRIYPGSGNTYYAQKFQG (SEQ ID NO: 14) and HCDR3 of GVYYLDY (SEQ ID NO: 18); and the VL region amino acid sequence comprises LCDR1 of RASQGIRTNVA (SEQ ID NO: 19), LCDR2 of SASYRQS (SEQ ID NO: 20) and LCDR3 of QQYNSYPRT (SEQ ID NO: 12);
(d) the VH region amino acid sequence comprises HCDR1 of GYTFTDYYMN (SEQ ID NO: 13), HCDR2 of MGRIYPGSGNTYYAQKFQG (SEQ ID NO: 14) and HCDR3 of GVYYFDE (SEQ ID NO: 21); and the VL region amino acid sequence comprises LCDR1 of RASQGVRINLA (SEQ ID NO: 22), LCDR2 of AASSRQS (SEQ ID NO: 23) and LCDR3 of QQYNSYPRT (SEQ ID NO: 12); or
(e) the VH region amino acid sequence comprises HCDR1 of GYTFTDFYMN (SEQ ID NO: 180), HCDR2 of MGRIYPASGNTYYAQKFQG (SEQ ID NO: 26) and HCDR3 of GVWYYDY (SEQ ID NO: 27); 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).
2. The antibody or antigen-binding portion of claim 1 , wherein:
(a) the VH region amino acid sequence comprises SEQ ID NO:189 and the VL region amino acid sequence comprises SEQ ID NO:190;
(b) the VH region amino acid sequence comprises SEQ ID NO:191 and the VL region amino acid sequence comprises SEQ ID NO:192;
(c) the VH region amino acid sequence comprises SEQ ID NO:193 and the VL region amino acid sequence comprises SEQ ID NO:194; or
(d) the VH region amino acid sequence comprises SEQ ID NO:195 and the VL region amino acid sequence comprises SEQ ID NO:196.
3. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is humanized or chimeric.
4. The antibody or antigen-binding portion of claim 1 , wherein the VH region, the VL region, or both the VH region and the VL region comprise one or more human framework region amino acid sequences.
5. The antibody or antigen-binding portion of claim 1 , wherein the VH region, the VL region, or both the VH region and the VL region comprise a human variable region framework scaffold amino acid sequence into which the CDRs have been inserted.
6. The antibody or antigen-binding portion 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 antibody or antigen-binding portion 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 antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion comprises an immunoglobulin constant region.
9. The antibody or antigen-binding portion of claim 8 , wherein the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY.
10. The antibody or antigen-binding portion of claim 9 , wherein the immunoglobulin constant region is IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2.
11. The antibody or antigen-binding portion of claim 8 , wherein the immunoglobulin constant region is immunologically inert.
12. The antibody or antigen-binding portion of claim 8 , 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, wherein numbering is according to the EU index as in Kabat.
13. The antibody or antigen-binding portion of claim 8 , 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 antibody or antigen-binding portion 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 antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is monoclonal.
16. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is tetrameric, tetravalent or multispecific.
17. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is a bispecific antibody or antigen-binding portion that binds specifically to a first antigen and a second antigen, wherein the first antigen is C-KIT and the second antigen is not C-KIT.
18. An immunoconjugate comprising the antibody or antigen-binding portion of claim 1 linked to a therapeutic agent.
19. The immunoconjugate of claim 18 , 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.
20. A pharmaceutical composition comprising the antibody or antigen-binding portion of claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.
21. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding portion of claim 1 , wherein the cancer is a gastrointestinal stromal cancer (GIST), a mast cell tumor, or acute myeloid leukemia.