Combination therapies comprising anti-erbb3 agents

Abstract

Disclosed are methods and compositions for inhibiting the growth of a tumor (e.g., a malignant tumor) in a subject. In particular, combination therapies for treating a tumor in a subject by co-administering an agent selected from i) an effective amount of an anti-estrogen agent; ii) an effective amount of a receptor tyrosine kinase inhibitor; iii) an effective amount of a MEK/PI3 kinase/AKT inhibitor; iv) an effective amount of MM-151; v) an effective amount of an mTOR inhibitor; and/or vi) an effective amount of trastuzumab or TMD1, and/or combinations thereof; and an effective amount of a bispecific anti-ErbB2/anti-ErbB3 antibody. Also disclosed is a bispecific anti-ErbB2/anti-ErbB3 antibody for use in the therapy of a tumor in combination with an agent selected from i) an effective amount of an anti-estrogen agent; ii) an effective amount of a receptor tyrosine kinase inhibitor; iii) an effective amount of a MEK/PI3 kinase/AKT inhibitor; iv) an effective amount of MM-151; v) an effective amount of an mTOR inhibitor; and/or vi) an effective amount of trastuzumab or TMD1, and/or combinations thereof.

1 .- 41 . (canceled) 
     
     
         42 . An aqueous solution comprising a bispecific anti-ErbB2/anti-ErbB3 antibody at a first concentration and an agent selected from one or more of i) an effective amount of an anti-estrogen agent; ii) an effective amount of a receptor tyrosine kinase inhibitor; iii) an effective amount of a MEK/P13 kinase/AKT inhibitor; iv) MM-151; v) an effective amount of an mTOR inhibitor; and/or vi) an effective amount of trastuzumab or ado-trastuzumab emtansine, at a second concentration, wherein each concentration is an effective concentration and when the aqueous solution is blood plasma in a subject, the subject does not experience a toxicity that is sufficiently harmful to require a change in a therapy being administered to the subject, which toxicity is mediated by a drug-drug interaction in the subject between the bispecific anti-ErbB2/anti-ErbB3 antibody and the agent. 
     
     
         43 .- 82 . (canceled) 
     
     
         83 . The aqueous solution of  claim 42 , wherein the anti-estrogen agent is fulvestrant or tamoxifen. 
     
     
         84 . The aqueous solution of  claim 42 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody comprises the amino acid sequence set forth in SEQ ID NO:1. 
     
     
         85 . The aqueous solution of  claim 42 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody is chosen from the group consisting of A5-HSA-ML3.9, ML3.9-HSA-A5, A5-HSA-B1 D2, B1 D2-HSA-A5, B12-HSA-B1D2, B1 D2-HSA-B12, A5-HSA-F5B6H2, F5B6H2-HSA-A5, H3-HSA-F5B6H2, F5B6H2-HSA-H3, F4-HSA-F5B6H2, F5B6H2-HSA-F4, B1 D2-HSA-H3, and H3-HSA-B1 D2. 
     
     
         86 . The aqueous solution of  claim 42 , wherein the receptor tyrosine kinase inhibitor is selected from the group consisting of erlotinib, afatinib, dasatinib, gefitinib, imatinib, pazopinib, lapatinib, sunitinib, nilotinib, and sorafenib. 
     
     
         87 . The aqueous solution of  claim 86 , wherein the receptor tyrosine kinase inhibitor is lapatinib. 
     
     
         88 . The aqueous solution of  claim 42 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody is MM-111. 
     
     
         89 . The aqueous solution of  claim 42 , wherein the subject is a human. 
     
     
         90 . The aqueous solution of  claim 42 , wherein the aqueous solution creates a substantially additive or superadditive effect. 
     
     
         91 . The aqueous solution of  claim 42 , wherein the anti-estrogen agent is letrozole, exemestane, anastrozole, aminoglutethimide, testolactone, vorozole, formestane, or fadrozole. 
     
     
         92 . The aqueous solution of  claim 42 , wherein the MEK/P13 kinase/AKT inhibitor is selected from one or more of selumetinib (AZD6244), buparlisib (BKM-120), pictilisib (GDC-0941), trametinib (GSK1120212), MK-2206, PD0325901, and triciribine, and combinations thereof. 
     
     
         93 . The aqueous solution of  claim 42 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody inhibits heregulin activation of ErbB2 and ErbB3. 
     
     
         94 . The aqueous solution of  claim 92 , wherein the aqueous solution comprises the bispecific anti-ErbB2/anti-ErbB3 antibody and trametinib. 
     
     
         95 . The aqueous solution of  claim 94 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody is at a first concentration and the trametinib is at a second concentration and when a first tissue culture medium is prepared comprising the bispecific anti-ErbB2/anti-ErbB3 antibody at the first concentration and the trametinib at the second concentration and is contacted with cancer cells of a cell line in a cell culture, cell growth or cell proliferation or production of pErbB3 or production of pAKT in the cells is inhibited as compared to when cells of the cell line in a cell culture are contacted with a second tissue culture medium that is essentially the same as the first medium except that it does not comprise the bispecific anti-ErbB2/anti-ErbB3 antibody. 
     
     
         96 . The aqueous solution of  claim 94 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         97 . The aqueous solution of  claim 94 , wherein the bispecific anti-ErbB2/anti-ErbB3 antibody is MM-111.