Anti-cea antibodies

Abstract

The present invention provides antigen binding molecules (ABMs) which bind membrane-bound CEA, including ABMs with improved therapeutic properties, and methods of using the same.

What is claimed is: 
     
         1 . An isolated antibody which binds membrane-bound CEA, wherein the antibody comprises a heavy chain variable region comprising:
 a heavy chain CDR1 selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:12,   a heavy chain CDR2 selected from the group consisting of SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24,   a heavy chain CDR3 selected from the group consisting of SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219 SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, and SEQ ID NO:224, and   a light chain CDR1 selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, and SEQ ID NO:45, and   a light chain CDR2 selected from the group consisting of SEQ ID NO:46, and SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, and SEQ ID NO:55, and   a light chain CDR3 of SEQ ID NO:56.   
     
     
         2 . The antibody of  claim 1 , wherein the heavy chain variable region comprises:
 the heavy chain CDR1 of SEQ ID NO:1,   the heavy chain CDR2 of SEQ ID NO:13,   a heavy chain CDR3 selected from the group consisting SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219 SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, and SEQ ID NO:224; and   wherein the light chain variable region comprises:   the light chain CDR1 of SEQ ID NO:39,   the light chain CDR2 of SEQ ID NO:49, and   the light chain CDR3 of SEQ ID NO:56.   
     
     
         3 . The antibody of  claim 2 , wherein the antibody comprises the framework residues of CH1A1A (SEQ ID NO: 261) or CH1A1B (SEQ ID NO: 262). 
     
     
         4 . The antibody of  claim 1 , wherein the antibody is stable at a temperature that is at least 0.5, 1.0, 1.5, or 2.0 degree Celcius higher than PR1A3 antibody or a humanized version of PR1A3 antibody. 
     
     
         5 . The antibody of  claim 4 , wherein the PR1A3 antibody or humanized version of PR1A3 antibody is a humanized version of PR1A3 antibody which comprises the heavy chain variable region CH7A (SEQ ID NO:101) and the light chain variable region 2F1 (SEQ ID NO: 209). 
     
     
         6 . The antibody of  claim 4 , wherein the increase in stability is measured using a dynamic light scattering assay. 
     
     
         7 . An isolated antibody which binds membrane-bound CEA, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 239, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 247 and a light chain variable region comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 209, and wherein the antibody has at least about 2-fold increase in stability as compared to PR1A3 or a humanized version of PR1A3. 
     
     
         8 . An isolated antibody which binds membrane-bound CEA, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 239, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, and SEQ ID NO: 247 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 209. 
     
     
         9 . The antibody of  claim 1 , wherein the antibody comprises an Fc region that has been glycoengineered. 
     
     
         10 . The antibody of  claim 9 , wherein at least about 20% to about 100% of the N-linked oligosaccharides in the Fc region are nonfucosylated. 
     
     
         11 . The antibody of  claim 9 , wherein at least about 20% to about 100% of the N-linked oligosaccharides in the Fc region are bisected. 
     
     
         12 . The antibody of  claim 9 , wherein at least about 20% to about 50% of the N-linked oligosaccharides in the Fc region are bisected, nonfucosylated. 
     
     
         13 . The antibody of  claim 9 , wherein the antibody has at least one increased effector function. 
     
     
         14 . The antibody of  claim 13 , wherein the at least one increased effector function is selected from the group consisting of: increased Fc receptor binding affinity, increased antibody-mediated cellular cytotoxicity (ADCC), increased binding to NK cells, increased binding to macrophages, increased binding to monocytes, increased binding to polymorphonuclear cells, direct signaling inducing apoptosis, increased dendritic cell maturation, and increased T cell priming. 
     
     
         15 . The antibody of  claim 14 , wherein the antibody has an increase in ADCC of at least about 40% to about 100% as compared to the non-glycoengineered parent antigen binding molecule. 
     
     
         16 . An isolated polynucleotide encoding the antibody of  claim 1 . 
     
     
         17 . A vector comprising the polynucleotide of  claim 16 . 
     
     
         18 . A host cell comprising the vector of  claim 17 . 
     
     
         19 . A composition comprising the antibody of  claim 14  and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of inducing cell lysis of a tumor cell, the method comprising contacting the tumor cell with the antibody of any of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the tumor cell is selected from the group consisting of a colorectal cancer cell, NSCLC (non-small cell lung cancer), gastric cancer cell, pancreatic cancer cell and breast cancer cell. 
     
     
         22 . The method of  claim 20 , wherein the cell lysis is induced by antibody dependent cell cytotoxicity of the antibody. 
     
     
         23 . A method of treating a subject having a cancer that abnormally expresses CEA, the method comprising administering to the subject a therapeutically effective amount of the antibody of  claim 1 . 
     
     
         24 . The method of  claim 24 , wherein the antibody is administered in combination with chemotherapy or radiation therapy.