SILENT Fc VARIANTS OF ANTI-CD40 ANTIBODIES

Abstract

The present invention relates to silent Fc variants of anti-CD40 antibodies and compositions and methods of use of said antibodies for treating pathological disorders such as autoimmune and inflammatory disorders and/or for preventing or reducing the risk of graft rejection in transplantation.

1 . An isolated antibody or a protein comprising an antigen-binding portion of an antibody directed against a target CD40 polypeptide (SEQ ID NO:28), characterized in that said antibody or protein
 a. binds to CD40 polypeptide with a K D  of 10 nM or less, and,   b. comprises a silent IgG Fc region.   
     
     
         2 . The isolated antibody or protein of  claim 1 , wherein said antibody or protein inhibits CD40L induced signalling with an IC50 of 50 ng/ml or less. 
     
     
         3 . The isolated antibody or protein of  claim 1 , wherein said antibody of protein has no or low agonist activity with respect to CD40 signalling. 
     
     
         4 . The isolated antibody or protein of  claim 1 , wherein said antibody or protein comprises a silent IgG Fc region selected from the group consisting of the amino acid sequence of SEQ ID NO:17, SEQ ID NO:18 or SEQ ID NO:19. 
     
     
         5 . The isolated antibody or protein according to  claim 1 , comprising heavy chain (V H ) and light chain (V L ) variable regions having at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent sequence identity to V H  of SEQ ID NO:9 and V L  of SEQ ID NO:10 respectively. 
     
     
         6 . The isolated antibody or protein according to  claim 1 , selected from the group consisting of:
 a. mAb1 antibody comprising heavy chain amino acid sequence of SEQ ID NO: 11 and light chain amino acid sequence of SEQ ID NO:12,   b. mAb2 antibody comprising heavy chain amino acid sequence of SEQ ID NO: 13 and light chain amino acid sequence of SEQ ID NO:14, and,   c. mAb3 antibody comprising heavy chain amino acid sequence of SEQ ID NO: 15 and light chain amino acid sequence of SEQ ID NO:16.   
     
     
         7 . The isolated antibody or protein according to  claim 1 , for use as a medicament. 
     
     
         8 . The isolated antibody or protein according to  claim 1 , for use in the treatment of autoimmune disorders and/or inflammatory disorders. 
     
     
         9 . The isolated antibody or protein according to  claim 1 , for use in preventing or reducing the risk of graft rejection in transplantation. 
     
     
         10 . The isolated antibody or protein according to  claim 7 , for use in the treatment of Multiple Sclerosis, Systemic Lupus Erythematosus, Sjögren's syndrome, Rheumatoid Arthritis, transplant rejection and graft-versus-host disease. 
     
     
         11 . A pharmaceutical composition, comprising an antibody or protein according to  claim 1 , in combination with at least a pharmaceutically acceptable excipient, diluent or carrier. 
     
     
         12 . The pharmaceutical composition of  claim 11 , additionally comprising other active ingredients. 
     
     
         13 . A liquid pharmaceutical formulation comprising an antibody or protein according to  claim 1  with at least a buffer. 
     
     
         14 . An isolated nucleic acid encoding the antibody or protein according to  claim 1 . 
     
     
         15 . A cloning or expression vector comprising one or more nucleic acids according to  claim 14 . 
     
     
         16 . A cloning or expression vector according to  claim 15  comprising at least one of the following coding sequences (a)-(c), operatively linked to suitable promoter sequences:
 (a) SEQ ID NO:22 and SEQ ID NO:23; 
 (b) SEQ ID NO:24 and SEQ ID NO:25; or, 
 (c) SEQ ID NO:26 and SEQ ID NO:27. 
 
     
     
         17 . A host cell comprising one or more cloning or expression vectors according to  claim 15 . 
     
     
         18 . A process for the production of an antibody or a protein of comprising an antigen-binding portion of an antibody directed against a target CD40 polypeptide (SEQ ID NO:28), characterized in that said antibody or protein
 a. binds to CD40 polypeptide with a K D  of 10 nM or less, and,   b. comprises a silent IgG Fc region,   
       the method comprising culturing the host cell of  claim 17 , purifying and recovering said antibody or protein.