C-KIT antibodies
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 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).
2. The antibody or antigen-binding portion 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 antibody or antigen-binding portion of claim 1 , wherein the antibody is human, humanized or chimeric.
4. The antibody or antigen-binding portion 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 antibody or antigen-binding portion 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 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 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.
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 antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is an Fab, an Fab′, an F(ab′) 2 , an Fd, an Fv, an scFv, a single domain antibody (dAb), a maxibody, a minibody, an intrabody, a diabody, a triabody, a tetrabody, a v-NAR or a bis-scFv.
15. The antibody or antigen-binding portion of claim 1 , wherein the antibody is monoclonal.
16. The antibody or antigen-binding portion 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. A pharmaceutical composition comprising the antibody or antigen-binding portion of claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.
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, an anti-angiogenic agent, an antiproliferative agent, a pro-apoptotic agent, a cytostatic enzyme, a cytolytic enzymes, a therapeutic nucleic acid, an anti-angiogenic agent, an anti-proliferative agent, or a pro-apoptotic agent.
20. A pharmaceutical composition comprising the immunoconjugate of claim 18 and a pharmaceutically acceptable carrier, diluent or excipient.
21. An isolated nucleic acid molecule encoding
the VH amino acid sequence and the VL region amino acid sequence of the antibody or antigen-binding portion of claim 1 .
22. An expression vector comprising the nucleic acid molecule of claim 21 .
23. A recombinant host cell comprising the nucleic acid molecule of claim 21 .
24. A recombinant host cell comprising the expression vector of claim 22 .