Antibodies to Carcinoembryonic Antigen (CEA), Methods of Making Same, and Uses Thereof

Abstract

The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies or variants thereof specific for cell surface or membrane bound human CEA. In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies with increased Fc receptor binding and increased effector function.

1 - 97 . (canceled) 
     
     
         98 . A composition comprising a first isolated polynucleotide sequence and a second isolated polynucleotide sequence, wherein said first isolated polynucleotide sequence is at least about 80% to about 100% identical to a sequence selected from the group consisting of: SEQ ID NOs: 113, 119, and 159-177, and wherein said second isolated polynucleotide sequence is at least about 80% to about 100% identical to a sequence selected from the group consisting of SEQ ID NOs: 117, 120, and 178-187, wherein said polynucleotides encode polypeptides that specifically bind to membrane-bound CEA with a monovalent K D  of no more than about 100 nM. 
     
     
         99 . The composition of  claim 98 , wherein said first isolated polynucleotide is SEQ ID NO: 119, and wherein said second isolated polynucleotide is SEQ ID NO:120. 
     
     
         100 . The composition of  claim 98 , wherein said first isolated polynucleotide encodes the polypeptide of SEQ ID NO: 107, and wherein said second isolated polynucleotide encodes the polypeptide of SEQ ID NO:108. 
     
     
         101 . An isolated polynucleotide encoding a polypeptide comprising an antigen binding domain that specifically binds membrane-bound human carcinoembryonic antigen (CEA) with a monovalent K D  of no more than about 100 nM, wherein said antigen binding domain comprises one or more complementarity determining region (CDR) sequences 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, SEQ ID NO:12, 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, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, 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, SEQ ID NO:45, SEQ ID NO:46, 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, SEQ ID NO:55, and SEQ ID NO:56, or a combination thereof. 
     
     
         102 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises one or more heavy chain CDR-encoding sequences selected from the group consisting of SEQ ID NOs:57-77. 
     
     
         103 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises one or more light chain CDR-encoding sequences selected from the group consisting of: SEQ ID NOs:78-98. 
     
     
         104 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises one or more heavy chain CDR-encoding sequences selected from the group consisting of SEQ ID NOs: 57-77 and one or more light chain CDR-encoding sequences selected from the group consisting of: SEQ ID NOs: 78-98. 
     
     
         105 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises:
 a) a sequence selected from the group consisting of: SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:61; and   b) a sequence selected from the group consisting of: SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66; and   c) a sequence selected from the group consisting of: SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, and SEQ ID NO:77.   
     
     
         106 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises the sequence of SEQ ID NO:119. 
     
     
         107 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises:
 a) a sequence selected from the group consisting of: SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, and SEQ ID NO:87; and   b) a sequence selected from the group consisting of: SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, and SEQ ID NO:97; and   c) SEQ ID NO:98.   
     
     
         108 . The isolated polynucleotide of  claim 101 , wherein said polynucleotide comprises the sequence of SEQ ID NO:120. 
     
     
         109 . A vector comprising the polynucleotide of  claim 101 . 
     
     
         110 . A vector comprising the polynucleotide of  claim 106 . 
     
     
         111 . A host cell comprising the vector of  claim 109 . 
     
     
         112 . A host cell comprising the vector of  claim 110 . 
     
     
         113 . A host cell comprising a first isolated polynucleotide and a second isolated polynucleotide, wherein said first isolated polynucleotide comprises a sequence selected from the group consisting of SEQ ID NOs:113, 119, and 159-177, and wherein said second isolated polynucleotide comprises a sequence selected from the group consisting of SEQ ID NOs: 117, 120, and 178-187. 
     
     
         114 . A method of producing an antigen binding molecule (ABM) that specifically binds membrane-bound human CEA, said method comprising:
 (a) culturing the host cell of  claim 111  in a medium under conditions allowing the expression of said polynucleotide, wherein said polynucleotide encodes a polypeptide that forms part of said ABM; and   (b) recovering said ABM.   
     
     
         115 . The method of  114 , wherein said ABM or a portion thereof binds the same epitope as, or is capable of competing for binding with the murine monoclonal antibody PR1A3. 
     
     
         116 . A method of producing an antigen binding molecule (ABM) that specifically binds membrane-bound human CEA, said method comprising:
 (a) culturing the host cell of  claim 112  in a medium under conditions allowing the expression of said polynucleotide, wherein said polynucleotide encodes a polypeptide that forms part of said ABM; and   (b) recovering said ABM.   
     
     
         117 . The method of  116 , wherein said ABM or a portion thereof binds the same epitope as, or is capable of competing for binding with the murine monoclonal antibody PR1A3.