Anti-EGFR Antibodies and Uses Thereof

Abstract

The present invention provides antibodies that bind to EGFR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human EGFR with high affinity. In certain embodiments, the antibodies of the present invention are capable of inhibiting the growth of tumor cells expressing high levels of EGFR and/or inducing antibody-dependent cell-mediated cytotoxicity (ADCC) of such cells. The antibodies of the invention are useful for the treatment of various cancers as well as other EGFR-related disorders.

What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment thereof that specifically binds dimeric human epidermal growth factor receptor (hEGFR) with a binding dissociation equilibrium constant (K D ) of less than about 20 pM as measured in a surface plasmon resonance assay at 37° C. 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds dimeric hEGFR with a dissociation half-life (t½) of greater than 400 minutes as measured in a surface plasmon resonance assay at 37° C. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof inhibits in vitro proliferation of cells expressing EGFR. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 3 , wherein the antibody or antigen-binding fragment thereof inhibits in vitro proliferation of cells expressing EGFR with an IC 50  of less than 200 pM. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 4 , wherein the antibody or antigen-binding fragment thereof induces antibody-dependent cell-mediated cytotoxicity (ADCC) of EGFR-expressing cells in the presence of peripheral blood mononuclear cells (PBMCs) with an EC 50  of less than 3.0 pM. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 5 , wherein the antibody or antigen-binding fragment thereof competes for binding to hEGFR with a reference antibody comprising an HCVR/LCVR sequence pair having SEQ ID NOs: 130/138. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 5 , wherein the antibody or antigen-binding fragment thereof binds to the same epitope on hEGFR as a reference antibody comprising an HCVR/LCVR sequence pair having SEQ ID NOs: 130/138. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof competes for binding to hEGFR with a reference antibody comprising an HCVR/LCVR sequence pair having SEQ ID NOs: 98/106. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the same epitope on hEGFR as a reference antibody comprising an HCVR/LCVR sequence pair having SEQ ID NOs: 98/106. 
     
     
         10 . An isolated antibody, or antigen-binding fragment thereof, that specifically binds human epidermal growth factor receptor (hEGFR), wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354 and 370; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362 and 378. 
     
     
         11 . The isolated antibody or antigen-binding fragment of  claim 10 , wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330, 338/346, 354/362 and 370/378. 
     
     
         12 . The isolated antibody or antigen-binding fragment of  claim 11 , wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 84-86-88-92-94-96; 100-102-104-108-110-112; 116-118-120-124-126-128; 132-134-136-140-142-144; 148-150-152-156-158-160; 164-166-168-172-174-176; 180-182-184-188-190-192; 196-198-200-204-206-208; 212-214-216-220-222-224; 228-230-232-236-238-240; 244-246-248-252-254-256; 260-262-264-268-270-272; 276-278-280-284-286-288; 292-294-296-300-302-304; 308-310-312-316-318-320; 324-326-328-332-334-336; 340-342-344-348-350-352; 356-358-360-364-366-368; and 372-374-376-380-382-384. 
     
     
         13 . An isolated antibody, or antigen-binding fragment thereof, that specifically binds human epidermal growth factor receptor (hEGFR), wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354 and 370; and (b) a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362 and 378. 
     
     
         14 . The isolated antibody or antigen-binding fragment of  claim 13 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330, 338/346, 354/362 and 370/378. 
     
     
         15 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 1 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         16 . A method for inhibiting tumor growth, the method comprising administering the pharmaceutical composition of  claim 15  to a subject afflicted with a tumor. 
     
     
         17 . The method of  claim 16 , wherein the tumor is selected from the group consisting of a renal tumor, a pancreatic tumor, a head and neck tumor, a breast tumor, a prostate tumor, a colon tumor, a gastric tumor, and ovarian tumor, a lung tumor, and a skin tumor. 
     
     
         18 . A method for inhibiting or attenuating tumor growth in a subject, the method comprising administering to the subject the pharmaceutical composition of  claim 15 , and a second therapeutic agent, wherein the second therapeutic agent is an antibody or antigen-binding fragment thereof that specifically binds HER2, ErbB3, ErbB4, cMet, IGF1R, Ang2, PDGFR-α or PDGFR-β. 
     
     
         19 . A method for inhibiting or attenuating tumor growth in a subject, the method comprising administering to the subject the pharmaceutical composition of  claim 15 , and a second therapeutic agent, wherein the second therapeutic agent is a VEGF antagonist.