Modified truncated complement system regulators

Abstract

Analogs of regulators of complement activation (RCA) proteins which have altered specificities and affinities for the targets C3b and/or C4b are described. These analogs are obtained by substituting amino acids which affect the complement inhibitory activities of these proteins, substituting, rearranging or adding SCRs (short consensus repeats) or SCR regions to the proteins, deleting amino acid sequences, and combinations thereof.

1 - 34 . (canceled) 
     
     
         35 . A modified form of a regulator of complement activation protein (RCA protein), wherein said RCA protein is selected from the group consisting of complement receptor 1, decay accelerating factor, membrane cofactor protein, C4 binding protein, factor H and any one of the foregoing RCA proteins wherein the carboxy terminus is removed to allow the RCA protein to be secreted;
 wherein said modified form is selected from the group consisting of:   a) a hybrid RCA protein comprising short consensus repeats (SCRs) of said RCA protein and SCRs from a different RCA protein selected from the group consisting of complement receptor 1, decay accelerating factor, membrane cofactor protein, C4 binding protein and factor H;   b) a recombined RCA protein in which the SCRs of said RCA protein are rearranged;   c) a truncated RCA protein consisting of three SCRs of said RCA protein; and   d) a modified RCA protein comprising any combination of a), b) and c),   wherein the modified form has complement regulatory activity.   
     
     
         36 . The modified form of a RCA protein of  claim 35 , wherein the complement regulatory activity is one or more activities selected from the group consisting of C3b binding activity, C4b binding activity, C3b and C4b binding activity, C3b cofactor activity, C4b cofactor activity, and decay accelerating activity. 
     
     
         37 . The modified form of a RCA protein of  claim 35 , wherein said modified form is a recombined RCA protein in which the SCRs of said RCA protein are rearranged. 
     
     
         38 . The modified form of a RCA protein of  claim 35 , wherein said modified form is a truncated RCA protein consisting of three SCRs of said RCA protein. 
     
     
         39 . A hybrid regulator of complement activation protein (RCA protein), wherein said hybrid RCA protein comprises:
 a) short consensus repeats (SCRS) of a first RCA protein selected from the group consisting of complement receptor 1, decay accelerating factor, membrane cofactor protein, C4 binding protein and factor H; and   b) SCRs from a different RCA protein selected from the group consisting of complement receptor 1, decay accelerating factor, membrane cofactor protein, C4 binding protein and factor H,   wherein said hybrid RCA protein has complement regulatory activity.   
     
     
         40 . The hybrid RCA protein of  claim 39 , wherein said first RCA protein is decay accelerating factor, and said different RCA protein is selected from the group consisting of complement receptor 1, membrane cofactor protein, C4 binding protein and factor H. 
     
     
         41 . The hybrid RCA protein of  claim 40 , wherein said different RCA protein is membrane cofactor protein. 
     
     
         42 . The hybrid RCA protein of  claim 41 , wherein said hybrid RCA protein comprises SCRs 2-3 of decay accelerating factor, and SCRs 1, 2, 3 and 4 of membrane cofactor protein. 
     
     
         43 . The hybrid RCA protein of  claim 42 , wherein said hybrid RCA protein has decay accelerating activity, and one or more additional complement regulatory activities selected from the group consisting of C3b binding activity, C4b binding activity, C3b and C4b binding activity, C3b cofactor activity, and C4b cofactor activity. 
     
     
         44 . The hybrid RCA protein of  claim 39 , wherein said hybrid RCA protein is soluble. 
     
     
         45 . An isolated DNA molecule that encodes the modified form of a RCA protein of  claim 35 . 
     
     
         46 . An expression vector comprising a DNA molecule that encodes the modified form of a RCA protein of  claim 35  operably linked to a control sequence compatible with a host cell. 
     
     
         47 . A recombinant host cell comprising the expression vector of  claim 46 . 
     
     
         48 . A nonhuman transgenic animal having a DNA molecule that encodes the modified form of a RCA protein of  claim 35  stably integrated into its genome. 
     
     
         49 . A method for making the modified form of a RCA protein any one of  claims 35 ,  39  and  40 , comprising expressing a DNA encoding said modified form of a RCA protein in a host cell. 
     
     
         50 . A pharmaceutical composition comprising the modified form of an RCA protein of  claim 35  and a pharmaceutically acceptable carrier. 
     
     
         51 . An isolated DNA molecule that encodes the hybrid RCA protein of  claim 39 . 
     
     
         52 . An expression vector comprising a DNA molecule that encodes the hybrid RCA protein of  claim 39  operably linked to a control sequence compatible with a host cell. 
     
     
         53 . A recombinant host cell comprising the expression vector of  claim 52 . 
     
     
         54 . A nonhuman transgenic animal having a DNA molecule that encodes the hybrid RCA protein of  claim 39  stably integrated into its genome. 
     
     
         55 . A method for making the hybrid RCA protein of  claim 39 , comprising expressing a DNA encoding said hybrid RCA protein in a host cell. 
     
     
         56 . A pharmaceutical composition comprising the hybrid RCA protein of  claim 39  and a pharmaceutically acceptable carrier. 
     
     
         57 . A hybrid regulator of complement activation protein (RCA protein), wherein said hybrid RCA protein comprises:
 a) short consensus repeats (SCRs) 2, 3 and 4 of decay accelerating factor; and   b) SCRs of a RCA protein selected from the group consisting of complement receptor 1, complement receptor 2, membrane cofactor protein, C4 binding protein and factor H,   wherein said hybrid RCA protein has decay accelerating activity and one or more activities selected from the group consisting of C3b binding activity, C4b binding activity, C3b and C4b binding activity, C3b cofactor activity, and C4b cofactor activity.   
     
     
         58 . The hybrid RCA protein of  claim 57 , wherein said hybrid RCA protein comprises SCRs of membrane cofactor protein. 
     
     
         59 . The hybrid RCA protein of  claim 58 , wherein said hybrid RCA protein comprises SCRs 3 and 4 of membrane cofactor protein. 
     
     
         60 . The hybrid RCA protein of  claim 59 , wherein said hybrid RCA protein comprises SCRs 2, 3 and 4 of membrane cofactor protein. 
     
     
         61 . The hybrid RCA protein of  claim 60 , wherein said hybrid RCA protein comprises SCRs 1, 2, 3 and 4 of membrane cofactor protein. 
     
     
         62 . The hybrid RCA protein of  claim 57 , wherein the hybrid RCA protein binds C3b and C4b and has C3b cofactor activity, C4b cofactor activity, and decay accelerating activity. 
     
     
         63 . The hybrid RCA protein of  claim 57 , wherein said hybrid RCA protein is soluble. 
     
     
         64 . An isolated DNA molecule that encodes the hybrid RCA protein of  claim 57 . 
     
     
         65 . An expression vector comprising a DNA molecule that encodes the hybrid RCA protein of  claim 57  operably linked to a control sequence compatible with a host cell. 
     
     
         66 . A recombinant host cell comprising the expression vector of  claim 65 . 
     
     
         67 . A method for making the hybrid RCA protein of  claim 57 , comprising expressing a DNA encoding said hybrid RCA protein in a host cell. 
     
     
         68 . A pharmaceutical composition comprising the hybrid RCA protein of  claim 57  and a pharmaceutically acceptable carrier.