Anti-cd40 antibodies

Abstract

The present invention related to new humanized antanogistic anti-CD40 antibodies and therapeutic and diagnostic methods and compositions for using the same.

What is claimed is: 
     
         1 . An isolated polynucleotide encoding a heavy chain variable region amino acid sequence or a light chain variable region, wherein the heavy chain variable region amino acid sequence comprises any of SEQ ID NO: 1 to 4, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO: 29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID. NO. 50, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73; and light chain variable region amino acid sequence comprises any of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76. 
     
     
         2 . An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36. 
     
     
         3 . An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain domain that is at least 95% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36. 
     
     
         4 . An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 to 4, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73, and a light chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76. 
     
     
         5 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide specifically binds to human CD40; has an antagonistic activity IC50 of less than 1 nM; or has no agonism up to 100 μg/ml in B cell proliferation. 
     
     
         6 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide has an in vivo half-life in non-human primates that is at least 10 days or has a half-life in cynomolgus monkeys of greater than 8 days at a dose of less than 30 mg/kg. 
     
     
         7 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide inhibits the growth or differentiation of cells of the CD40-associated disorder. 
     
     
         8 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide does not stimulate production of cytokines from B cells in the absence of CD40L. 
     
     
         9 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide inhibits production of cytokines from B cells in the absence of CD40L. 
     
     
         10 . The isolated polynucleotide of  claim 2 , wherein the antibody or antigen binding fragment encoded by the polynucleotide binds to human CD40 in the presence of 50% human serum with a reduction of on rate less than two fold. 
     
     
         11 . A method of making an antibody or antigen binding fragment thereof comprising expressing the polynucleotide of  claim 2  in a recombinant host cell culture. 
     
     
         12 . The method of  claim 11 , wherein the host cell is a mammalian host cell. 
     
     
         13 . The method of  claim 12 , wherein the mammalian host cell is selected from the group consisting of a human embryonic kidney line, a baby hamster kidney cell (BHK), a Chinese hamster ovary cells/-DHFR1 (CHO), a mouse sertoli cell, a monkey kidney cells, an African green monkey kidney cell, a human cervical carcinoma cell, a canine kidney cell, a buffalo rat liver cell, a human lung cell, a human liver cell, a mouse mammary tumor cell, a TR1 cell, a MRC 5 cell, a FS4 cell, and a human hepatoma cell. 
     
     
         14 . A vector comprising the polynucleotide of  claim 2 . 
     
     
         15 . The vector of  claim 14  further comprising at least one of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, or a transcription termination sequence. 
     
     
         16 . The vector of  claim 14 , wherein the vector is suitable for expression in a mammalian host cell.