Humanized anti-erbb2 antibodies and treatment with anti-erbb2 antibodies

Abstract

The present application describes humanized anti-ErbB2 antibodies and methods for treating cancer with anti-ErbB2 antibodies, such as humanized anti-ErbB2 antibodies.

1 . A method of treating cancer in a human, wherein the cancer expresses epidermal growth factor receptor (EGFR), comprising administering to the human a therapeutically effective amount of an antibody which binds ErbB2. 
     
     
         2 . The method of  claim 1  wherein the antibody blocks ligand activation of an ErbB receptor. 
     
     
         3 . The method of  claim 2  wherein the antibody blocks binding of monoclonal antibody 2C4 to ErbB2. 
     
     
         4 . The method of  claim 1  wherein the cancer is characterized by excessive activation of EGFR. 
     
     
         5 . The method of  claim 4  wherein the cancer overexpresses an ErbB ligand. 
     
     
         6 . The method of  claim 5  wherein the ErbB ligand is transforming growth factor alpha (TGF-α). 
     
     
         7 . The method of  claim 1  wherein the antibody blocks TGF-α activation of mitogen-activated protein kinase (MAPK). 
     
     
         8 . The method of  claim 1  wherein the cancer is not characterized by overexpression of ErbB2 receptor. 
     
     
         9 . The method of  claim 1  wherein the cancer is selected from the group consisting of colon, rectal and colorectal cancer. 
     
     
         10 . The method of  claim 9  further comprising administering a chemotherapeutic agent to the human. 
     
     
         11 . The method of  claim 10  wherein the chemotherapeutic agent is selected from the group consisting of 5-fluorouracil (5-FU), leucovorin (LV), CPT-11, and levamisole. 
     
     
         12 . The method of  claim 1  wherein the cancer is lung cancer. 
     
     
         13 . The method of  claim 12  wherein the cancer is non-small cell lung cancer. 
     
     
         14 . The method of  claim 12  further comprising administering a chemotherapeutic agent to the human. 
     
     
         15 . The method of  claim 14  wherein the chemotherapeutic agent is selected from the group consisting of a taxane, gemcitabine, navelbine, cisplatin, oxaliplatin, and carboplatin. 
     
     
         16 . The method of  claim 1  wherein the antibody has a biological characteristic of monoclonal antibody 2C4. 
     
     
         17 . The method of  claim 16  wherein the antibody comprises monoclonal antibody 2C4 or humanized 2C4. 
     
     
         18 . The method of  claim 1  wherein the antibody is an antibody fragment. 
     
     
         19 . The method of  claim 18  wherein the antibody fragment is a Fab fragment. 
     
     
         20 . The method of  claim 1  wherein the antibody is not conjugated with a cytotoxic agent. 
     
     
         21 . The method of  claim 18  wherein the antibody fragment is not conjugated with a cytotoxic agent. 
     
     
         22 . The method of  claim 1  wherein the antibody is conjugated with a cytotoxic agent. 
     
     
         23 . The method of  claim 1  further comprising administering to the human a therapeutically effective amount of a second therapeutic agent selected from the group consisting of a second different antibody which binds ErbB2, a chemotherapeutic agent, an EGFR-targeted drug, an anti-angiogenic agent, an anti-hormonal compound, a cardioprotectant, and a cytokine. 
     
     
         24 . The method of  claim 1  comprising administering at least one dose of the antibody to the human in an amount from about 0.5 mg/kg to about 10 mg/kg. 
     
     
         25 . The method of  claim 24  comprising administering the dose about every week. 
     
     
         26 . The method of  claim 24  comprising administering the dose about every three weeks. 
     
     
         27 . A method of treating cancer in a human, wherein the cancer is not characterized by overexpression of the ErbB2 receptor, comprising administering to the human a therapeutically effective amount of an antibody which binds to ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         28 . The method of  claim 27  wherein the cancer is breast cancer. 
     
     
         29 . The method of  claim 28  wherein the cancer is metastatic breast cancer. 
     
     
         30 . The method of  claim 28  further comprising administering a chemotherapeutic agent to the human. 
     
     
         31 . The method of  claim 30  wherein the chemotherapeutic agent is selected from the group consisting of an anthracycline antibiotic, cyclophosphomide, a taxane, navelbine, xeloda, mitomycin C, oxaliplatin, gemcitabine, and a platinum compound. 
     
     
         32 . A method of treating cancer in a human comprising administering to the human therapeutically effective amounts of (a) a first antibody which binds ErbB2 and inhibits growth of cancer cells which overexpress ErbB2; and (b) a second antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         33 . The method of  claim 32  wherein the first antibody comprises monoclonal antibody 4D5 or humanized 4D5 and the second antibody comprises monoclonal antibody 2C4 or humanized 2C4. 
     
     
         34 . A method of treating cancer in a human, wherein the cancer is selected from the group consisting of colon, rectal and colorectal cancer, comprising administering to the human a therapeutically effective amount of an antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         35 . An article of manufacture comprising a container and a composition contained therein, wherein the composition comprises an antibody which binds ErbB2, and further comprising a package insert indicating that the composition can be used to treat cancer which expresses epidermal growth factor receptor (EGFR). 
     
     
         36 . An article of manufacture comprising a container and a composition contained therein, wherein the composition comprises an antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor, and further comprising a package insert indicating that the composition can be used to treat cancer, wherein the cancer is not characterized by overexpression of the ErbB2 receptor. 
     
     
         37 . An article of manufacture comprising (a) a first container with a composition contained therein, wherein the composition comprises a first antibody which binds ErbB2 and inhibits growth of cancer cells which overexpress ErbB2; and (b) a second container with a composition contained therein, wherein the composition comprises a second antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         38 . The article or manufacture of  claim 37  further comprising a package insert indicating that the first and second antibody compositions can be used to treat cancer. 
     
     
         39 . An article of manufacture comprising a container and a composition contained therein, wherein the composition comprises an antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor, and further comprising a package insert indicating that the composition can be used to treat a cancer selected from the group consisting of colon, rectal and colorectal cancer. 
     
     
         40 . A humanized antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         41 . The humanized antibody of  claim 40  which binds ErbB2 essentially as effectively as murine monoclonal antibody 2C4. 
     
     
         42 . The humanized antibody of  claim 40  comprising a variable heavy (V H ) domain which comprises nonhuman hypervariable region residues incorporated into a human V H  domain and further comprises a framework region (FR) substitution at a position selected from the group consisting of 69H, 71H and 73H, utilizing the numbering system set forth in Kabat (1991). 
     
     
         43 . The humanized antibody of  claim 42  comprising FR substitutions at positions 69H, 71H and 73H. 
     
     
         44 . The humanized antibody of  claim 40  comprising V H  domain complementarity determining region (CDR) residues GFTFTDYTMX (SEQ ID NO:7); DVNPNSGGSIYNQRFKG (SEQ ID NO:8); and NLGPSFYFDY (SEQ ID NO:9). 
     
     
         45 . The humanized antibody of  claim 40  comprising the V H  domain amino acid sequence in SEQ ID NO:4. 
     
     
         46 . The humanized antibody of  claim 40  comprising variable light (V L ) domain complementarity determining region (CDR) residues KASQDVSIGVA (SEQ ID NO:10); SASYXXX (SEQ ID NO:11); and QQYYIYPYT (SEQ ID NO:12). 
     
     
         47 . The humanized antibody of  claim 40  comprising the V 1 , domain amino acid sequence in SEQ ID NO:3. 
     
     
         48 . The humanized antibody of  claim 40  which is an intact IgG1 antibody. 
     
     
         49 . The humanized antibody of  claim 40  which is an antibody fragment. 
     
     
         50 . The humanized antibody of  claim 49  which is a Fab fragment. 
     
     
         51 . An affinity matured antibody which binds ErbB2 and blocks ligand activation of an ErbB receptor. 
     
     
         52 . A composition comprising the humanized antibody of  claim 40  and a pharmaceutically acceptable carrier. 
     
     
         53 . An immunoconjugate comprising the humanized antibody of  claim 40  conjugated with a cytotoxic agent. 
     
     
         54 . Isolated nucleic acid encoding the humanized antibody of  claim 40 . 
     
     
         55 . A vector comprising the nucleic acid of  claim 54 . 
     
     
         56 . A host cell comprising the vector of  claim 55 . 
     
     
         57 . A process of producing a humanized antibody comprising culturing the host cell of  claim 56  so that the nucleic acid is expressed. 
     
     
         58 . The process of  claim 57  further comprising recovering the humanized antibody from the host cell culture. 
     
     
         59 . The process of  claim 58  wherein the humanized antibody is recovered from the host cell culture medium.