Antibody that binds ErbB-2 and ErbB-3
The invention relates among others to antibodies comprising a first antigen-binding site that binds Erb B-2 and a second antigen-binding site that binds Erb B-3. The antibodies can typically reduce a ligand-induced receptor function of Erb B-3 on a Erb B-2 and Erb B-3 positive cell. Also described are method for the treatment and use of the antibodies in imaging and in the treatment of subjects having an Erb B-2, Erb B-3 or Erb B-2/3 positive tumor.
1. A bispecific antibody comprising a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences of AYYIN (SEQ ID NO:49), RIYPGSGYTSYAQKFQG (SEQ ID NO:50), and PPVYYDSAWFAY (SEQ ID NO:51) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences GYYMH (SEQ ID NO:64), WINPNSGGTNYAQKFQG (SEQ ID NO:65), and DHGSRHFWSYWGEFDY (SEQ ID NO:66) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87.
2. The bispecific antibody of claim 1 , which is afucosylated in order to enhance antibody dependent cellular cytotoxicity (ADCC).
3. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains.
4. The bispecific antibody of claim 3 , wherein the compatible heterodimerization domains are compatible immunoglobulin heavy chain CH3 heterodimerization domains.
5. A pharmaceutical composition comprising the bispecific antibody of claim 1 .
6. A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor the method comprising: administering to the subject the antibody of claim 1 or the pharmaceutical composition of claim 5 .
7. A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor, the method comprising:
administering to the subject:
the bispecific antibody of claim 1 , and
at least one additional therapeutic agent.
8. The bispecific antibody of claim 1 , wherein the antibody comprises the light chain variable region comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLOSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNEYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 87).
9. The method of claim 7 , wherein said at least one additional therapeutic agent is selected from afatinib, laptinib, neratinib, BYL719, MK-2206, everolimus, saracatinib, paclitaxel, vorinostat.
10. The bispecific antibody of claim 1 , wherein the first binding arm comprises a heavy chain variable region comprising SEQ ID NO: 48, the second binding arm comprises a heavy chain variable region comprising SEQ ID NO: 63, and both the first and second binding arms comprise a light chain variable region comprising SEQ ID NO: 87.
11. The bispecific antibody of claim 1 , wherein the first binding arm comprises a heavy chain comprising SEQ ID NO: 88, the second binding arm comprises a heavy chain comprising SEQ ID NO: 89, and both the first and second binding arms comprise a light chain comprising SEQ ID NO: 87.
12. The method of claim 6 , wherein the tumor is a ErbB-2/ErbB-3 positive tumor.
13. The method of claim 6 , wherein the tumor is a ErbB-2 positive tumor.
14. The method of claim 6 , wherein the tumor is a ErbB-3 positive tumor.
15. The method of claim 7 , wherein the tumor is a ErbB-2/ErbB-3 positive tumor.
16. The method of claim 7 , wherein the tumor is a ErbB-2 positive tumor.
17. The method of claim 7 , wherein the tumor is a ErbB-3 positive tumor.