Inhibitors Of Complement Activation

Abstract

The invention relates to factor D inhibitors, which bind to factor D and block the functional activity of factor D in complement activation. The inhibitors include antibody molecules, as well as homologues, analogues and modified or derived forms thereof, including immunoglobulin fragments like Fab, F(ab′) 2 and Fv, small molecules, including peptides, oligonucleotides, peptidomimetics and organic compounds. A monoclonal antibody which bound to factor D and blocked its ability to activate complement was generated and designated 166-32. The hybridoma producing this antibody was deposited at the American Type Culture Collection, 10801 University Blvd., Manassas, Va. 20110-2209, under Accession Number HB-12476.

1 . An inhibitor of complement activation which specifically binds factor D which at a molar ratio of about 1.5:1 (inhibitor: factor D) can substantially inhibit complement activation. 
     
     
         2 . (canceled) 
     
     
         3 . The inhibitor of  claim 1  wherein the inhibition of complement activation is determined in vitro. 
     
     
         4 . The inhibitor of  claim 1  wherein the inhibition of complement activation is determined in vitro by an extracorporeal assay. 
     
     
         5 . An inhibitor of complement activation which binds to a region of human factor D between (and including) amino acid residue numbers Cys154 and Cys170. 
     
     
         6 . The inhibitor of  claim 5  which does not bind to human factor D if amino acid residues Arg156, His159 and Leu168 are absent. 
     
     
         7 . The inhibitor of  claim 1  which is an antibody or a homologue, analogue or fragment thereof, a peptide, a peptidomimetic or an organic compound. 
     
     
         8 . The inhibitor of  claim 7  wherein the antibody fragment is Fab, F(ab′) 2 , Fv or single chain Fv. 
     
     
         9 . The inhibitor of  claim 7  wherein the antibody is a chimeric, humanized, deimmunised or human antibody. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A monoclonal antibody or a fragment, analogue or homologue thereof, or a peptide, oligonucleotide, peptidomimetic or an organic compound which binds to the same epitope on factor D as the antibody 166-32. 
     
     
         13 . The fragment of  claim 12  which is an are Fab, F(ab′) 2 , Fv or single chain Fv. 
     
     
         14 . The chimeric form, having a mouse variable region and a human constant region, of the Fab fragment of  claim 13 . 
     
     
         15 . (canceled) 
     
     
         16 . A cell line producing the fragment of  claim 13 . 
     
     
         17 . A cell line producing the chimeric Fab fragment of  claim 14 . 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method of treating diseases or conditions that are mediated by excessive or uncontrolled activation of the complement system comprising administering, in vivo or ex vivo, an inhibitor according to  claim 1 . 
     
     
         21 . A method of treating complement-mediated conditions associated with cardiopulmonary bypass comprising administering, in vivo or ex vivo, an inhibitor according to  claim 1 .