Anti-her antibodies

Abstract

The invention provides anti-HER antibodies, including multispecific anti-HER antibodies, compositions comprising and methods of using these antibodies. Also provided herein are EGFR/HER3 multispecific antibodies that are less toxic than traditional EGFR antagonists.

1 . A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the toxicity of the antibody is less than the toxicity of an EGFR antagonist. 
     
     
         2 . The antibody of  claim 1 , wherein the toxicity is dermatological toxicity. 
     
     
         3 . The antibody of  claim 1 , wherein the EGFR antagonist is cetuximab. 
     
     
         4 . The antibody of  claim 1 , wherein the antibody inhibits a biological activity of at least one of EGFR and HER3 
     
     
         5 . The antibody of  claim 2 , wherein the antibody inhibits EGF binding to EGFR. 
     
     
         6 . The antibody of  claim 2 , wherein the antibody inhibits TGF-α induced EGFR phosphorylation. 
     
     
         7 . The antibody of  claim 1 , wherein the antibody inhibits tumor cell growth. 
     
     
         8 . The antibody of  claim 1 , wherein the antibody binds to domain III of EGFR. 
     
     
         9 . The antibody of  claim 1 , wherein the antibody binds to EGFR and HER3 with a Kd of less than 10 −6  M. 
     
     
         10 . The antibody of  claim 9 , wherein the antibody binds to EGFR with a Kd of less than 10 −6  M and binds to HER3 with a Kd of less than 10 −7  M. 
     
     
         11 . The antibody of  claim 1 , wherein the antibody comprises
 (a) HVR-H1 comprising the amino acid sequence of LSGDWIH (SEQ ID NO: 48);   (b) HVR-H2 comprising the amino acid sequence of VGEISAAGGYTD (SEQ ID NO: 51); and   (c) HVR-H3 comprising the amino acid sequence of ARESRVSFEAAMDY (SEQ ID NO: 53); and   (d) HVR-L1 comprising the amino acid sequence of NIATDVA (SEQ ID NO: 55);   (e) HVR-L2 comprising the amino acid sequence of SASF (SEQ ID NO: 56); and   (f) HVR-L3 comprising the amino acid sequence of SEPEPYT (SEQ ID NO: 57).   
     
     
         12 . The antibody of  claim 1 , comprising
 (a) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30;   (b) a light chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 29; or   (c) a heavy chain variable domain as in (a) and a light chain variable domain as in (b).   
     
     
         13 . The antibody of  claim 12 , comprising a heavy chain variable domain of SEQ ID NO: 30. 
     
     
         14 . The antibody of  claim 12 , comprising a light chain variable domain sequence of SEQ ID NO: 29. 
     
     
         15 . A multispecific antibody comprising a heavy chain variable domain sequence of SEQ ID NO: 30 and a light chain variable domain sequence of SEQ ID NO: 29. 
     
     
         16 . The antibody of  claim 1 , wherein the antibody is a full length IgG1 antibody. 
     
     
         17 . Isolated nucleic acid encoding the antibody of  claim 1 . 
     
     
         18 . A host cell comprising the nucleic acid of  claim 17 . 
     
     
         19 . A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the antibody comprises
 (a) HVR-H1 comprising the amino acid sequence of LSGDWIH (SEQ ID NO: 48);   (b) HVR-H2 comprising the amino acid sequence of VGEISAAGGYTD (SEQ ID NO: 51); and   (c) HVR-H3 comprising the amino acid sequence of ARESRVSFEAAMDY (SEQ ID NO: 53); and   (d) HVR-L1 comprising the amino acid sequence of NIATDVA (SEQ ID NO: 55);   (e) HVR-L2 comprising the amino acid sequence of SASF (SEQ ID NO: 56); and   (f) HVR-L3 comprising the amino acid sequence of SEPEPYT (SEQ ID NO: 57).   
     
     
         20 . A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the antibody comprises
 (a) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30;   (b) a light chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 29; or   (c) a heavy chain variable domain as in (a) and a light chain variable domain as in (b).   
     
     
         21 . The antibody of  claim 20  comprising a heavy chain variable domain of SEQ ID NO: 30. 
     
     
         22 . The antibody of  claim 20 , comprising a light chain variable domain sequence of SEQ ID NO: 29. 
     
     
         23 . A method of producing an antibody comprising culturing the host cell of  claim 18  so that the antibody is produced. 
     
     
         24 . An immunoconjugate comprising the antibody of  claim 1  and a cytotoxic agent. 
     
     
         25 . A pharmaceutical formulation comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         26 . A method of treating an individual having cancer comprising administering to the individual an effective amount of the antibody of  claim 1 . 
     
     
         27 . The antibody of  claim 26 , wherein the cancer comprises cells that express EGFR and HER3. 
     
     
         28 . The antibody of  claim 26 , wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, and non-small lung cell cancer. 
     
     
         29 . A method of inhibiting a biological activity of a HER receptor in an individual comprising administering to the individual an effective amount of the antibody of  claim 1  to inhibit a biological activity of a HER receptor.