Factor h potentiating antibodies and uses thereof

Abstract

The invention relates to isolated, synthetic or recombinant antibodies and fragments thereof specific for factor H. The invention further relates to the use of such antibodies and fragments for inhibiting complement activation and treatment of disorders associated with complement activation.

1 . An isolated, synthetic or recombinant antibody or fragment thereof that specifically binds to complement control protein domain 18 (CCP18) of factor H (FH) and potentiates FH activity, wherein said FH activity is inhibition of alternative complement activation, and wherein said antibody or fragment thereof comprises:
 a heavy chain CDR1 having the sequence of SEQ ID NO:5, a heavy chain CDR2 having the sequence of SEQ ID NO:6 and a heavy chain CDR3 sequence having the sequence of SEQ ID NO:7, and/or   a light chain CDR1 sequence having the sequence of SEQ ID NO:1, a light chain CDR2 sequence having the sequence of SEQ ID NO:2 and a light chain CDR3 having the sequence of SEQ ID NO:3.   
     
     
         2 . The antibody or fragment according to  claim 1  wherein inhibition of alternative complement activation comprises:
 an inhibition of hemolytic activity, 
 an inhibition of complement component (C3) deposition on cells of said individual, and/or 
 an increase of binding of FH to C3b, iC3b and/or C3d. 
 
     
     
         3 . The antibody or fragment according to  claim 1  or  2  wherein said fragment comprises at least a Fab fragment. 
     
     
         4 . The antibody or fragment according to any one of  claims 1 - 3  that is a monoclonal antibody or fragment thereof. 
     
     
         5 . The antibody or fragment according to any one of  claims 1 - 4  that is a chimeric or humanized antibody or fragment thereof, comprising human light chain and heavy chain constant regions. 
     
     
         6 . The antibody or fragment according to any one of  claims 1 - 5  comprising a heavy chain sequence comprising a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO:8 and/or a light chain sequence comprising a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO:4. 
     
     
         7 . An isolated, synthetic or recombinant antibody or fragment thereof that competes for binding to complement control protein domain 18 (CCP18) of factor H (FH) with an antibody comprising a heavy chain sequence comprising the sequence of SEQ ID NO:8 and a light chain sequence comprising the sequence of SEQ NO:4 and that potentiates FH activity, wherein said FH activity is inhibition of alternative complement activation. 
     
     
         8 . An isolated, synthetic or recombinant nucleic acid molecule comprising a nucleic acid sequence encoding the antibody or fragment according to any one of  claims 1 - 6 . 
     
     
         9 . The nucleic acid molecule according to  claim 8  comprising:
 a heavy chain CDR1 sequence comprising a sequence which is at least 80% identical to the sequence of SEQ ID NO:13, and/or 
 a heavy chain CDR2 sequence comprising a sequence which is at least 80% identical to the sequence of SEQ ID NO:14, and/or 
 a heavy chain CDR3 sequence comprising a sequence which is at least 80% identical to the sequence of SEQ ID NO:15, and/or 
 a light chain CDR1 sequence comprising a sequence which is at least80% identical to the sequence of SEQ ID NO:9, and/or 
 a light chain CDR2 sequence comprising a sequence which is at least 80% identical to the sequence of SEQ ID NO:10, and/or 
 a light chain CDR3 sequence comprising a sequence which is at least 80% identical to the sequence of SEQ ID NO:11. 
 
     
     
         10 . The nucleic acid molecule according to  claim 8  or  9  comprising a heavy chain sequence comprising a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO:16 and/or comprising a light chain sequence comprising a sequence which has at least 80% sequence identity to the sequence of SEQ NO:12. 
     
     
         11 . A vector comprising a nucleic acid molecule according to any one of  claims 8 - 10 . 
     
     
         12 . A recombinant cell comprising a nucleic acid molecule or vector according to any one of  claims 8 - 11 . 
     
     
         13 . A pharmaceutical composition comprising an antibody or fragment according to any one of  claims 1 - 7 , or a nucleic acid molecule according to any one of  claims 8 - 10 , or a vector according to  claim 11 , and a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         14 . An antibody or fragment according to any one of  claims 1 - 7  or a nucleic acid molecule or vector according to any one of  claim 8 - 11  for use in therapy. 
     
     
         15 . An antibody or fragment, a nucleic acid molecule or vector for use according to  claim 14  for use in inhibiting alternative complement activation. 
     
     
         16 . An antibody or fragment according to any one of  claims 1 - 7  or a nucleic acid molecule or vector according to any one of  claim 8 - 11  for use in the treatment, alleviation or prevention of a disorder associated with alternative pathway complement activation. 
     
     
         17 . Use of an antibody or fragment according to any one of  claims 1 - 7 , a nucleic acid molecule according to any one of  claims 8 - 10 , or a vector according to  claim 11  for the preparation of a medicament for the treatment, alleviation or prevention of a disorder associated with alternative pathway complement activation. 
     
     
         18 . A method for treating, alleviating or preventing a disorder associated with alternative pathway complement activation comprising administering to an individual in need thereof a therapeutically effective amount of an antibody or fragment according to any one of  claims 1 - 7 , a nucleic acid molecule according to any one of  claims 8 - 10 , a vector according to  claim 11 , or a pharmaceutical composition according to  claim 13 . 
     
     
         19 . An antibody or fragment, nucleic acid molecule or vector for use according to  claim 16 , a use according to  claim 17  or a method according to  claim 18 , wherein said disorder is selected from the group consisting of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranoproliferative glomerulonephritis (MPGN). 
     
     
         20 . A method for inhibiting alternative complement activation comprising administering to an individual an antibody or fragment according to any one of  claims 1 - 7 , a nucleic acid molecule according to any one of  claims 8 - 10 , or a vector according to  claim 11 . 
     
     
         21 . A method for producing an antibody or fragment according to any one of  claims 1 - 6 , the method comprising providing a cell with a nucleic acid molecule or a vector according to any one of  claims 8 - 11 , and allowing said cell to translate the nucleic acid sequence comprised by said nucleic acid molecule or vector, thereby producing said antibody or fragment according to any one of  claims 1 - 6 , preferably further comprising harvesting, purifying and/or isolating said antibody or fragment according to any one of  claims 1 - 6 . 
     
     
         22 . A method according to  claim 21  further comprising harvesting, purifying and/or isolating said antibody or fragment according to any one of  claims 1 - 6 .