Anti C-MET antibodies
Provided herein are antibody molecules that bind specifically to C-MET and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.
1. An anti-C-MET 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 GYTFTSYTMH (SEQ ID NO: 34), HCDR2 of MGIINPSGGSTSYAQKFQG (SEQ ID NO: 35) and HCDR3 of QEITTEFDY (SEQ ID NO: 36); and the VL region amino acid sequence comprises LCDR1 of RASQSVSSYANSYLH (SEQ ID NO: 37), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKSEPLT (SEQ ID NO: 39);
(b) the VH region amino acid sequence comprises HCDR1 of GYTFTSYTMH (SEQ ID NO: 34), HCDR2 of MGWINPSGGLANYAQKFQG (SEQ ID NO: 54) and HCDR3 of SEITTDFDY (SEQ ID NO: 55); and the VL region amino acid sequence comprises LCDR1 of RASQSVDSYANSYLH (SEQ ID NO: 51), LCDR2 of RGSTRES (LCDR2; SEQ ID NO: 38) and LCDR3 of QQSKSEPLT (SEQ ID NO: 39);
(c) the VH region amino acid sequence comprises HCDR1 of GYTFTSYTMH (SEQ ID NO: 34), HCDR2 of MGWINPSGGSTSYAQKFQG (SEQ ID NO: 40) and HCDR3 of QEITTEFDY (SEQ ID NO: 36); and the VL region amino acid sequence comprises LCDR1 of RASQSVSSYANSYLH (SEQ ID NO: 37), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKSEPLT (SEQ ID NO: 39);
(d) the VH region amino acid sequence comprises HCDR1 of GYTFTSYAMH (SEQ ID NO: 41), HCDR2 of MGWINPSGGSTSYAQKFQG (SEQ ID NO: 40) and HCDR3 of QEITTEFDY (SEQ ID NO: 36); and the VL region amino acid sequence comprises LCDR1 of RASQSVSSYANSYLH (SEQ ID NO: 37), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKSEPLT (SEQ ID NO: 39);
(e) the VH region amino acid sequence comprises HCDR1 of GYTFTSYTMH (SEQ ID NO: 34), HCDR2 of MGWINPNGGSTSYAQKFQG (SEQ ID NO: 42) and HCDR3 of QEITTEFDY (SEQ ID NO: 36); and the VL region amino acid sequence comprises LCDR1 of RASQSVSSYANSYLH (SEQ ID NO: 37), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKSEPLT (SEQ ID NO: 39);
(f) the VH region amino acid sequence comprises HCDR1 of GYIFTSYSMH (SEQ ID NO: 43), HCDR2 of MGWINPSNGLANYAQKFQG (SEQ ID NO: 44) and HCDR3 of QEITTEFDI (SEQ ID NO: 45); and the VL region amino acid sequence comprises LCDR1 of RASQSVESYAQSYLH (SEQ ID NO: 46), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKSDPLT (SEQ ID NO: 76);
(g) the VH region amino acid sequence comprises HCDR1 of GYIFTSYTMH (SEQ ID NO: 48), HCDR2 of MGWINPNGGLASYAQKFQG (SEQ ID NO: 49) and HCDR3 of SEITTEQDY (SEQ ID NO: 50); and the VL region amino acid sequence comprises LCDR1 of RASQSVDSYANSYLH (SEQ ID NO: 51), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQSKESPLT (SEQ ID NO: 47); or
(h) the VH region amino acid sequence comprises HCDR1 of GYIFTSYTMH (SEQ ID NO: 48), HCDR2 of MGWINPNGGSTSYAQKFQG (SEQ ID NO: 42) and HCDR3 of QEITTEFDY (SEQ ID NO: 36); and the VL region amino acid sequence comprises LCDR1 of RASQSVESYANSYLH (SEQ ID NO: 52), LCDR2 of RGSTRES (SEQ ID NO: 38) and LCDR3 of QQYGSEPLT (SEQ ID NO: 53).
2. The antibody or antigen-binding portion of claim 1 , wherein
(a) the VH region amino acid sequence comprises SEQ ID NO:7 and the VL region amino acid sequence comprises SEQ ID NO:8; or
(b) the VH region amino acid sequence comprises SEQ ID NO:9 and the VL region amino acid sequence comprises SEQ ID NO:10.
3. The antibody or antigen-binding portion of claim 1 , wherein the antibody 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 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 IGKV3-20 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 8 , wherein the immunoglobulin constant region comprises any one of SEQ ID NOS: 11-17.
11. 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.
12. The antibody or antigen-binding portion of claim 1 , wherein the antibody is monoclonal.
13. The antibody or antigen-binding portion of claim 1 , wherein the antibody is a tetrameric antibody, a tetravalent antibody or a multispecific antibody.
14. The antibody or antigen-binding portion of claim 1 , wherein the antibody is a bispecific antibody that binds specifically to a first antigen and a second antigen, wherein the first antigen is C-MET and the second antigen is not C-MET.
15. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion binds specifically to (a) human C-MET or (b) human C-MET and cynomolgus C-MET.
16. The antibody or antigen-binding portion of claim 1 , wherein the antibody or antigen-binding portion is in a human IgG4 format comprising the amino acid substitution S228P, and wherein the antibody or antigen-binding portion has
(a) a melting temperature (Tm) from about 77° C. to about 81° C.; and/or
(b) an isoelectric point (pI) greater than about pH 7.4.
17. A pharmaceutical composition comprising the antibody or antigen-binding portion of claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.
18. A nucleic acid molecule encoding
(a) the VH region amino acid sequence;
(b) the VL region amino acid sequence; or
(c) both the VH and the VL region amino acid sequences of the antibody or antigen-binding portion of claim 1 .
19. An expression vector comprising the nucleic acid molecule of claim 18 .