Agents targeting cd138 and uses thereof

Abstract

Disclosed is a human murine chimeric antibody which substantially retains the antigen binding region of its murine counterpart and displays improved binding affinities to the antigen and/or more homogenous binding to target cells.

1 . An engineered targeting antibody which recognizes CD138 comprising:
 a heavy chain comprising amino acids 31-35 of SEQ ID NO: 1 (CDR1), amino acids 51-68 of SEQ ID NO: 1 (CDR2) and amino acids 99-111 of SEQ ID NO: 1 (CDR3), and   a light chain comprising amino acids 24-34 of SEQ ID NO: 2 (CDR1), amino acids 50-56 of SEQ ID NO: 2 (CDR2) and amino acids 89-97 of SEQ ID NO. 2 (CDR3), wherein the engineered targeting antibody is of an IgG4 isotype.   
     
     
         2 . The engineered targeting antibody of  claim 1 , wherein said antibody is a chimeric human/mouse antibody. 
     
     
         3 . The engineered targeting antibody of  claim 1  further comprising:
 (a) amino acid residues 123 to 448 of SEQ ID NO: 1, and/or 
 (b) amino acid residues 108 to 214 of SEQ ID NO: 2. 
 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The engineered targeting antibody of  claim 1  further comprising:
 (a) amino acid residues 123 to 448 of SEQ ID NO: 1, and/or 
 (b) amino acid residues 108 to 214 of SEQ ID NO: 2, respectively or mutations thereof that
 (i) maintain or lower the antibody-dependent cytotoxicity and/or complement-dependent cytotoxicity of the engineered targeting antibody and/or 
 (ii) stabilize the engineered targeting antibody. 
 
 
     
     
         9 . The engineered targeting antibody of  claim 8  wherein: (i) the mutations that lower the antibody-dependent cytotoxicity and/or complement-dependent cytotoxicity of the engineered targeting antibody are mutations at IgG4 residue positions 327, 330 and 331; and/or (ii) the mutations that stabilize the engineered targeting antibody are leucine-to-glutamic acid mutations in a CH2 region of IgG4 and serine-to-proline exchanges in a IgG4 hinge core. 
     
     
         10 . The engineered targeting antibody of  claim 1 , wherein the heavy chain variable region comprises amino acid residues 1-122 of SEQ ID NO: 1; and/or the light chain variable region comprises amino acid residues 1-107 of SEQ ID NO: 2. 
     
     
         11 . The engineered targeting antibody of  claim 1 , wherein said light chain has at least about 70% sequence identity with SEQ ID NO:2 and all CDRs are maintained. 
     
     
         12 . The engineered targeting antibody of  claim 11 , wherein
 (a) said heavy chain has at least about 90% sequence identity with SEQ ID NO:1; and   (b) said light chain has at least about 90% sequence identity with SEQ ID NO:2 and all CDRs are maintained.   
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising the antibody of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         15 . A Chinese hamster ovary cell line which produces the antibody of  claim 1  and is deposited und deposit No. DSM ACC2875 at the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH. 
     
     
         16 . (canceled) 
     
     
         17 . An isolated polypeptide comprising an amino acid sequence of an immunoglobulin heavy chain comprising amino acid residues 31 to 35 (CDR1), 51 to 68 (CDR2) and 99 to 111 (CDR3) of SEQ ID NO:1 and having at least 90% sequence identity with SEQ ID NO: 1, wherein a constant region of the immunoglobulin heavy chain is an IgG4 isotype constant region, and wherein a targeting antibody comprising said immunoglobulin heavy chain targets CD138. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The isolated polypeptide of  claim 18  wherein said immunoglobulin light chain has at least at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:2. 
     
     
         21 . An isolated polypeptide according to  claim 17 , wherein said immunoglobulin heavy chain is identical to the sequence of SEQ ID NO:1. 
     
     
         22 . An isolated polypeptide according to  claim 21 , wherein said immunoglobulin light chain is identical to the sequence of SEQ ID NO:2. 
     
     
         23 .- 24 . (canceled)