Antibodies for epidermal growth factor receptor 3 (her3)

Abstract

This invention relates to antibodies or fragments thereof which interact with HER family of receptors, e.g., HER3 receptor. In particular, it relates to antibodies or fragments thereof that recognize a conformational epitope of HER3 receptor comprising residues from both domains 2 and 4 resulting in inhibition of both ligand-dependent and ligand-independent signal transduction; and allow ligand binding (e.g., neuregulin), whilst preventing ligand-induced activation of signal transduction. These antibodies or fragments can be used to treat a number of diseases or disorders characterized by increased levels of HER3 expression (e.g., esophageal cancer). These antibodies or fragments can be used to treat a number of diseases or disorders characterized by the antibodies or fragments ability to decrease tissue weight (e.g., prostate or uterine weights) or to induce atrophy of tissue (e.g., atrophy of male breast).

We claim: 
     
         1 . A method of treating a disorder characterized by increased levels of HER3 expression in an esophageal tract comprising:
 selecting patient suffering from increased levels of HER3 expression in an esophageal tract; and   administering an antibody or fragment thereof that specifically binds to a HER3 receptor, such that the antibody or fragment thereof binds to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor and blocks both ligand-dependent and ligand-independent signal transduction, thereby treating the disorder.   
     
     
         2 . The method of  claim 1 , wherein the disorder is selected from the group consisting of esophageal cancer and Barretts esophageal cancer. 
     
     
         3 . The method of  claim 1 , wherein the antibody or fragment thereof is administered by a route selected from the group consisting of oral, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal administration. 
     
     
         4 . The method of  claim 1 , wherein the antibody or fragment is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier, excipient, or diluent. 
     
     
         5 . The method of  claim 4 , further comprising an additional therapeutic agent. 
     
     
         6 . The method of  claim 5 , wherein the additional therapeutic agent is selected from the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the additional therapeutic agent is a HER1 inhibitor selected from the group consisting of Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the group consisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945 Å (Genentech), MOR10703 (Novartis) and small molecules that inhibit HER3; and a HER4 inhibitor. 
     
     
         8 . The method of  claim 6 , wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669, everolimus/Affinitor®. 
     
     
         9 . The method of  claim 6 , wherein the additional therapeutic agent is a PI3 Kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719. 
     
     
         10 . A method of treating gastric cancer comprising:
 selecting a patient suffering from gastric cancer; and   administering an antibody or fragment thereof that specifically binds to a HER3 receptor, such that the antibody or fragment thereof binds to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor and blocks both ligand-dependent and ligand-independent signal transduction, thereby treating gastric cancer.   
     
     
         11 . The method of  claim 10 , wherein the antibody or fragment thereof is administered by a route selected from the group consisting of oral, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal administration. 
     
     
         12 . The method of  claim 10 , wherein the antibody or fragment is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier, excipient, or diluent. 
     
     
         13 . The method of  claim 12 , further comprising an additional therapeutic agent. 
     
     
         14 . The method of  claim 13 , wherein the additional therapeutic agent is selected from the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the additional therapeutic agent is a HER1 inhibitor selected from the group consisting of Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the group consisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945 Å (Genentech), MORI0703 (Novartis) and small molecules that inhibit HER3; and a HER4 inhibitor. 
     
     
         16 . The method of  claim 14 , wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669, everolimus/Affinitor®. 
     
     
         17 . The method of  claim 14 , wherein the additional therapeutic agent is a PI3 Kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719. 
     
     
         18 . A method of treating head and neck cancer comprising:
 selecting a patient suffering from cancer the head and neck; and   administering an antibody or fragment thereof that specifically binds to a HER3 receptor, such that the antibody or fragment thereof binds to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor and blocks both ligand-dependent and ligand-independent signal transduction, thereby treating head and neck cancer.   
     
     
         19 . The method of  claim 18 , wherein the antibody or fragment thereof is administered by a route selected from the group consisting of oral, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal administration. 
     
     
         20 . The method of  claim 18 , wherein the antibody or fragment is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier, excipient, or diluent. 
     
     
         21 . The method of  claim 20 , further comprising an additional therapeutic agent. 
     
     
         22 . The method of  claim 21 , wherein the additional therapeutic agent is selected from the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor. 
     
     
         23 . The method of  claim 22 , wherein the additional therapeutic agent is a HER1 inhibitor selected from the group consisting of Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the group consisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945 Å (Genentech), MORI0703 (Novartis) and small molecules that inhibit HER3; and a HER4 inhibitor. 
     
     
         24 . The method of  claim 22 , wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669, everolimus/Affinitor®. 
     
     
         25 . The method of  claim 22 , wherein the additional therapeutic agent is a PI3 Kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719. 
     
     
         26 . A method of treating gynacomastica, comprising:
 selecting a patient suffering from gynacomastica; and   administering an antibody or fragment thereof that specifically binds to a HER3 receptor, such that the antibody or fragment thereof binds to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor and blocks both ligand-dependent and ligand-independent signal transduction, thereby treating gynacomastica.   
     
     
         27 . The method of  claim 26 , wherein the antibody or fragment thereof is administered by a route selected from the group consisting of oral, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal administration. 
     
     
         28 . The method of  claim 26 , wherein the antibody or fragment is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier, excipient, or diluent. 
     
     
         29 . The method of  claim 26 , further comprising an additional therapeutic agent. 
     
     
         30 . The method of  claim 29 , wherein the additional therapeutic agent is selected from the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor. 
     
     
         31 . The method of  claim 30 , wherein the additional therapeutic agent is a HER1 inhibitor selected from the group consisting of Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the group consisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945 Å (Genentech), MORI0703 (Novartis) and small molecules that inhibit HER3; and a HER4 inhibitor. 
     
     
         31 . The method of  claim 30 , wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669, everolimus/Affinitor®. 
     
     
         32 . The method of  claim 30 , wherein the additional therapeutic agent is a PI3 Kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719. 
     
     
         33 . A method of treating endometriosis comprising:
 selecting a patient suffering from endometriosis; and   administering an antibody or fragment thereof that specifically binds to a HER3 receptor, such that the antibody or fragment thereof binds to a conformational epitope comprising amino acid residues within domain 2 and domain 4 of the HER3 receptor and blocks both ligand-dependent and ligand-independent signal transduction, thereby treating endometriosis.   
     
     
         34 . The method of  claim 33 , wherein the antibody or fragment thereof is administered by a route selected from the group consisting of oral, subcutaneous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal administration. 
     
     
         35 . The method of  claim 34 , wherein the antibody or fragment is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier, excipient, or diluent. 
     
     
         36 . The method of  claim 35 , further comprising an additional therapeutic agent. 
     
     
         37 . The method of  claim 36 , wherein the additional therapeutic agent is selected from the group consisting of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor. 
     
     
         38 . The method of  claim 37 , wherein the additional therapeutic agent is a HER1 inhibitor selected from the group consisting of Matuzumab (EMD72000), Erbitux®/Cetuximab, Vectibix®/Panitumumab, mAb 806, Nimotuzumab, Iressa®/Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016), Tykerb®/Lapatinib Ditosylate, Tarceva®/Erlotinib HCL (OSI-774), PKI-166, and Tovok®; a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate/Tykerb®; a HER3 inhibitor selected from the group consisting of, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945 Å (Genentech), MORI0703 (Novartis) and small molecules that inhibit HER3; and a HER4 inhibitor. 
     
     
         39 . The method of  claim 37 , wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus/Torisel®, ridaforolimus/Deforolimus, AP23573, MK8669, everolimus/Affinitor®. 
     
     
         40 . The method of  claim 39 , wherein the additional therapeutic agent is a PI3 Kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719.