Humanized antibodies to LIV-1 and use of same to treat cancer
View Patent ↗The invention provides humanized antibodies that specifically bind to LIV-1. The antibodies are useful for treatment and diagnoses of various cancers as well as detecting LIV-1.
1. A humanized antibody, that specifically binds human LIV-1 comprising a mature heavy chain variable region comprising three CDRs of SEQ ID NO:53 and having an amino acid sequence at least 95% identical to SEQ ID NO:53 provided that position H27 is occupied by L, position H29 is occupied by I, H30 by E and H94 by V and a mature light chain variable region comprising three CDRs of SEQ ID NO:60 at least 95% identical to SEQ ID NO:60 provided position L36 is occupied by Y and position L46 by P.
2. The humanized antibody of claim 1 , further provided position H76 is occupied by N.
3. The humanized antibody of claim 1 wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.
4. The humanized antibody of claim 3 , wherein the heavy chain constant region is a mutant form of a natural human constant region which has reduced binding to an Fcgamma receptor relative to the natural human constant region.
5. The humanized antibody of claim 3 , wherein the heavy chain constant region is of IgG1 isotype.
6. The humanized antibody of claim 3 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:44 and the light chain constant region has an amino acid sequence comprising SEQ ID NO:42.
7. The humanized antibody of claim 3 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:46 (S239C) and the light chain constant region has an amino acid sequence comprising SEQ ID NO:42.
8. The humanized antibody of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:52 or 53 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 59 or 60.
9. The humanized antibody of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:53 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:60.
10. The humanized antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent.
11. The humanized antibody of claim 1 , having an association constant for human or cynomolgus monkey LIV-1 of 0.5 to 2×10 9 M −1 .
12. A nucleic acid encoding a mature heavy chain variable region and/or a mature light chain variable region as defined by claim 1 .
13. A method of treating a patient having a cancer expressing LIV-1, comprising administering to the patient an effective regime of a humanized antibody of claim 1 .
14. The method of claim 13 , wherein the cancer is a breast cancer, a prostate cancer, a cervical cancer or a melanoma.
15. A pharmaceutical composition comprising a humanized antibody of claim 1 .
16. The method of claim 13 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent.
17. The method of claim 13 , wherein the isotype of the antibody is human IgG1.