Pharmaceutical antibody compositions with resistance to soluble cea

Abstract

The present invention relates to pharmaceutical compositions for the treatment of an epithelial tumor in a human, said pharmaceutical composition comprising an IgG1 antibody specifically binding to human CEA, wherein the variable region of said IgG1 antibody comprises at least (i) a CDR-H1 having the amino acid sequence “SYWMH” (SEQ ID NO: 29) and a CDR-H2 having the amino acid sequence “FIRNKANGGTTEYAASVKG” (SEQ ID NO: 28) and a CDR-H3 having the amino acid sequence “DRGLRFYFDY” (SEQ ID NO: 27) or (ii) a CDR-H1 having the amino acid sequence “TYAMH” (SEQ ID NO: 31) and a CDR-H2 having the amino acid sequence “LISNDGSNKYYADSVKG” (SEQ ID NO: 30) and a CDR-H3 having the amino acid sequence “DRGLRFYFDY” (SEQ ID NO: 27). Furthermore, processes for the production of said pharmaceutical compositions as well as medical/pharmaceutical uses for the IgG1 antibody molecules bearing specificities for the human CEA antigen are disclosed.

1 . A pharmaceutical composition for the treatment of an epithelial tumor in a human, said pharmaceutical composition comprising an IgG1 antibody specifically binding to human CEA, wherein the variable region of said IgG1 antibody comprises at least the amino acid sequences selected from the group consisting of:
 (a) a CDR-H1 having the amino acid sequence “SYWMH” (SEQ ID NO. 29) and a CDR-H2 having the amino acid sequence “FIRNKANGGTTEYAASVKG” (SEQ ID NO. 28) and a CDR-H3 having the amino acid sequence “DRGLRFYFDY” (SEQ ID NO. 27) and   (b) a CDR-H1 having the amino acid sequence “TYAMH” (SEQ ID NO. 31) and a CDR-H2 having the amino acid sequence “LISNDGSNKYYADSVKG” (SEQ ID NO. 30) and a CDR-H3 having the amino acid sequence “DRGLRFYFDY” (SEQ ID NO. 27).   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said variable region comprises a CDR-L1 having the amino acid sequence “TLRRGINVGAYSIY” (SEQ ID NO. 34) and/or a CDR-L2 having the amino acid sequence “YKSDSDKQQGS” (SEQ ID NO. 33) and/or a CDR-L3 having the amino acid sequence “MIWHSGASAV” (SEQ ID NO. 32). 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the light chain constant region of said IgG1 antibody is a lambda light chain constant region. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the amino acid sequence of the VH region of the variable region of said IgG1 antibody is SEQ ID NO. 20, 22 or 24. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the amino acid sequence of the VL region of the variable region of said IgG1 antibody is SEQ ID NO. 26. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the variable region of said IgG1 antibody is selected from the group consisting of:
 (a) the VH region consists of the amino acid sequence shown in SEQ ID NO. 22 and the VL region consists of the amino acid sequence shown in SEQ ID NO. 26;   (b) the VH region consists of the amino acid sequence shown in SEQ ID NO. 20 and the VL region consists of the amino acid sequence shown in SEQ ID NO. 26; and   (c) the VH region consists of the amino acid sequence shown in SEQ ID NO. 24 and the VL region consists of the amino acid sequence shown in SEQ ID NO. 26.   
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein said IgG1 antibody comprises an amino acid sequence selected from the group consisting of:
 (a) an amino acid sequence of the heavy chain shown in SEQ ID NO. 77 and an amino acid sequence of the light chain shown in SEQ ID NO. 80;   (b) an amino acid sequence of the heavy chain shown in SEQ ID NO. 78 and an amino acid sequence of the light chain shown in SEQ ID NO. 80;   (c) an amino acid sequence of the heavy chain shown in SEQ ID NO. 79 and an amino acid sequence of the light chain shown in SEQ ID NO. 80; and   an amino acid sequence at least 85% identical, more preferred at least 90% identical, most preferred at least 95% identical to the amino acid sequence of (a), (b) or (c).   
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein said epithelial tumor is a gastrointestinal adenocarcinoma, a breast adenocarcinoma or a lung adenocarcinoma. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said gastrointestinal adenocarcinoma is a colorectal, pancreatic, an oesophageal or a gastric adenocarcinoma. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition is for the treatment of progressive tumors, late stage tumors, tumor patients with high tumor load/burden, metastatic tumors, or tumor patients with a CEA serum concentration higher than 100 ng/ml. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the IgG1 antibody is CDR grafted, humanized and/or deimmunized. 
     
     
         12 . A pharmaceutical composition comprising a nucleic acid sequence encoding an IgG1 antibody as defined in  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising a vector which comprises a nucleic acid sequence as defined in  claim 12 . 
     
     
         14 . A pharmaceutical composition comprising a vector which comprises a nucleic acid as defined in  claim 12 , wherein said vector further comprises a regulatory sequence which is operably linked to said nucleic acid sequence defined in  claim 12 . 
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein said vector is an expression vector. 
     
     
         16 . A pharmaceutical composition comprising a host transformed or transfected with a nucleic acid defined in  claim 12  or a vector which comprises a nucleic acid as defined in  claim 12 . 
     
     
         17 . A process for the production of a pharmaceutical composition according to  claim 1 , said process comprising culturing a host transformed or transfected with a nucleic acid sequence encoding an IgG1 antibody as defined in  claim 1  under conditions allowing the expression of the IgG1 antibody as defined in  claim 1  and recovering the produced IgG1 antibody from the culture. 
     
     
         18 . The pharmaceutical composition of  claim 1 , which is further comprising suitable formulations of carriers, stabilizers and/or excipients. 
     
     
         19 .- 23 . (canceled) 
     
     
         24 . A method for the prevention, treatment or amelioration of an epithelial tumor in a subject in the need thereof, said method comprising the step of administration of an effective amount of a pharmaceutical composition  claim 1 , over a sufficient period of time. 
     
     
         25 . The method of  claim 24 , wherein said epithelial tumor is a gastrointestinal adenocarcinoma, a breast adenocarcinoma or a lung adenocarcinoma. 
     
     
         26 . The method of  claim 25 , wherein said gastrointestinal adenocarcinoma is a colorectal, pancreatic, an oesophageal or a gastric adenocarcinoma. 
     
     
         27 . The method of  claim 24 , wherein the pharmaceutical composition is for the treatment of progressive tumors, late stage tumors, tumor patients with high tumor load/burden, metastatic tumors, or tumor patients with a CEA serum concentration higher than 100 ng/ml. 
     
     
         28 . The method of  claim 24 , wherein said pharmaceutical composition is administered in combination with an additional drug. 
     
     
         29 . The method of  claim 28 , wherein said drug is a non-proteinaceous compound or a proteinaceous compound. 
     
     
         30 . A method for the prevention, treatment or amelioration of an epithelial tumor in a subject in the need thereof said method comprising the step of administration of an effective amount of a pharmaceutical composition  claim 1 , over a sufficient period of time, wherein said pharmaceutical composition is administered in combination with an additional drug, and wherein said proteinaceous compound or non-proteinaceous compound is administered simultaneously or non-simultaneously with an IgG1 antibody as defined in  claim 1 , a nucleic acid molecule, comprising a nucleic acid encoding an IgG1 antibody as defined in  claim 1 , a vector which comprises a nucleic acid sequence comprising a nucleic acid encoding an IgG1 antibody as defined in  claim 1 , or a host transformed or transfected with a nucleic acid sequence encoding an IgG1 antibody as defined in  claim 1 . 
     
     
         31 . The method of  claim 24 , wherein said subject is a human. 
     
     
         32 . A kit comprising an IgG1 antibody as defined in  claim 1 , a nucleic acid molecule comprising a nucleic acid encoding an IgG1 antibody as defined in  claim 1 , a vector which comprises a nucleic acid sequence comprising a nucleic acid encoding an IgG1 antibody as defined in  claim 1 , or a host transformed or transfected with a nucleic acid sequence encoding an IgG1 antibody as defined in  claim 1 . 
     
     
         33 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition is for the treatment of progressive tumors, late stage tumors, tumor patients with high tumor load/burden, metastatic tumors, or tumor patients with a CEA serum concentration higher than 100 ng/ml, or, a method for the prevention, treatment or amelioration of an epithelial tumor in a subject in the need thereof, said method comprising the step of administration of an effective amount of a pharmaceutical composition of  claim 1 , over a sufficient period of time, wherein the pharmaceutical composition is for the treatment of progressive tumors, late stage tumors, tumor patients with high tumor load/burden, metastatic tumors, or tumor patients with a CEA serum concentration higher than 100 ng/ml, and wherein said CEA serum concentration is determined by ELISA.