Cytotoxic antibodies directed against antibodies inhibiting factor viii

Abstract

The invention relates to an anti-idiotypical antibody targeting an antibody inhibiting the human fact VIII, said inhibiting antibody targeting the C2 region of the human factor VIII, the variable region of each of the light chains thereof being encoded by a sequence of nucleic acids of which at least 70% is identical to the murine sequence of nucleic acids SEQ ID NO: 1, and the variable region of each of the heavy chains thereof being encoded by a sequence of nucleic acids of which at least 70% is identical to the murine sequence of nucleic acids SEQ ID NO: 2, the constant regions of the light chains and the heavy chains being constant regions from a non-murine species. The invention also relates to the use of said antibody for activating the FcγRIII receptors of cytotoxic immune cells, and to the production of a medicament especially for the treatment of haemophilia A.

1 . An anti-idiotypic monoclonal antibody directed against an antibody inhibiting human factor VIII (FVIII), said inhibiting antibody being directed against the C2 region of human FVIII, wherein the variable region of each of said anti-idiotypic antibody's light chains is encoded by the murine nucleic acid sequence SEQ ID NO: 1, the variable region of each of said anti-idiotypic antibody's heavy chains is encoded by the murine nucleic acid sequence SEQ ID NO: 2, the constant regions of said anti-idiotypic antibody's light chains and heavy chains are constant regions originating from a non-murine species, and wherein the fucose level/galactose level ratio of the glycan structures of said anti-idiotypic antibody, present on the glycosylation site of the Fe region, is less than or equal to 0.6. 
     
     
         2 . The anti-idiotypic monoclonal antibody according to  claim 1 , wherein said FVIII inhibiting antibody is the antibody BO2C11. 
     
     
         3 . The anti-idiotypic monoclonal antibody according to  claim 1 , wherein the constant regions of each of said anti-idiotypic antibody's light chains and each of said anti-idiotypic antibody's heavy chains are human constant regions. 
     
     
         4 . The anti-idiotypic monoclonal antibody according to  claim 1  or  3 , wherein the constant region of each of said anti-idiotypic antibody's light chains is of type κ. 
     
     
         5 . The anti-idiotypic monoclonal antibody according to  claim 4 , wherein the constant region of each of said anti-idiotypic antibody's heavy chains is of type γ. 
     
     
         6 . The anti-idiotypic monoclonal antibody according to  claim 5 , wherein the constant region of each of said anti-idiotypic antibody's heavy chains is of type γ1. 
     
     
         7 . The anti-idiotypic monoclonal antibody according to  claim 6 , wherein the constant region of each of said anti-idiotypic antibody's heavy chains is of type γ1 and is encoded by the human nucleic acid sequence SEQ ID NO: 3 and wherein the constant region of each of said anti-idiotypic antibody's light chains is encoded by the human nucleic acid sequence SEQ ID NO: 4. 
     
     
         8 . A stable cell line expressing an antibody according to  claim 1 . 
     
     
         9 . The stable cell line according to  claim 8  chosen from the group consisting of: SP2/0, YB2/0, IR983F, the human myeloma Namalwa, PER.C6, the CHO lines, in particular CHO-K-1, CHO-Lec10, CHO-Lec1, CHO-Lec13, CHO Pro-5, CHO dhfr−, Wil-2, Jurkat, Vero, MoIt-4, COS-7, 293-HEK, BHK, K6H6, NSO, SP2/0-Ag 14 and P3X63Ag8.653. 
     
     
         10 . Clone R565 deposited under registration number I-3510 in the Collection Nationale de Cultures de Microorganismes. 
     
     
         11 . A pharmaceutical composition comprising an anti-idiotypic monoclonal antibody according to  claim 1  and one or more excipients and/or pharmaceutically acceptable vehicles.