Compositions and methods to inhibit formation of the C5b-9 complex of complement

Abstract

Compounds modulating CD59 mediated complement activity, compositions including these compounds, and methods of making and using the compounds are disclosed, which are based on the identification of the hu CD59 amino acid residues which serve as the binding site for CD59-C9 interactions. These residues correspond to amino acid residues 42-58, and bind to the region of C9 corresponding to human 334-418, more specifically, between amino acid residues 359 and 384. Compounds can be derived using this basic amino acid sequence and corresponding three dimensional structure within the protein using any of several techniques known to those skilled in the art, including rational drug design using computer data bases and modeling of peptide/protein-ligand binding, antibodies and anti-idiotypic antibodies generated to the proteins or peptides containing this peptide sequence, and modified peptides. Those compounds imitating the structure and/or function of the peptide region are referred to herein as “peptidomimetics”, and include small molecules which present the surface exposed side chains in these amino acids in the same relative positions, compounds identified by combinatorial chemistry techniques which bind to the active portions of human C9, as well as modified peptides. The compounds can be used to inhibit complement by binding to C9 analogously to CD59, or to maintain complement inhibition, by blocking CD59 binding to C9. The compounds can be administered locally or systemically in any suitable carrier in an amount effective to either inhibit complement or block the inhibition of complement, in a patient in need of treatment thereof.

We claim:  
     
         1 . A compound that specifically inhibits the formation of the hu C5b-9 complex selected from the group consisting of molecules structurally mimicking CD59 amino acid residues 42 to 58 when they are in a spatial orientation which inhibits formation of the hu C5b-9 complex, wherein the compound is not hu CD59.  
     
     
         2 . The compound of  claim 1 , selected from the group consisting of proteins, peptides, nucleic acids, and small molecules which bind specifically to amino acids 359 to 384 of hu C9.  
     
     
         3 . The compound of  claim 2 , wherein the protein is an antibody.  
     
     
         4 . The compound of  claim 2 , wherein the protein is a chimeric peptide which includes the amino acids 42 to 58 of the human sequence of CD59.  
     
     
         5 . The compound of  claim 2 , wherein the peptide is a covalently cyclized peptide comprising hu CD59 amino acid residues 42 to 58.  
     
     
         6 . The compound of  claim 2 , wherein the composition is a peptide of less than forty amino acids residues including amino acid residues 42 to 58 of hu CD59.  
     
     
         7 . The compound of  claim 1 , further comprising a pharmaceutically acceptable carrier for administration to patients in need thereof.  
     
     
         8 . The compound of  claim 1  wherein the compound is a peptidomimetic compound comprising the side chains of hu CD59 amino acid residues His 44 , Asn 48 , Asp 49 , Thr 51 , Thr 52 , Arg 55 , and Glu 58  in an equivalent spacial orientation and alignment to that presented on the surface of hu CD59.  
     
     
         9 . The compound of  claim 8  wherein the spacial orientation and alignment of the side chains of His 44 , Asn 48 , Asp 49 , Thr 51 , Thr 52 , Arg 55 , and Glu 58  in the compound are equivalent to the spacial orientation and alignment deduced by NMR structure determination.  
     
     
         10 . A method for inhibiting C5b-9 complex assembly comprising administering to a patient in need thereof an effective amount of a composition to increase CD59 inhibition of C5b-9 complex assembly wherein the composition includes a compound selected from the group consisting of molecules structurally mimicking CD59 amino acid residues 42 to 58 which bind to C9 wherein the compound is not hu CD59.  
     
     
         11 . The method of  claim 10 , wherein the compound is selected from the group consisting of proteins, peptides, nucleic acids, and small molecules which bind specifically to amino acids 359 to 384 of hu C9.  
     
     
         12 . The method of  claim 11 , wherein the protein is an antibody.  
     
     
         13 . The method of  claim 11 , wherein the protein is a chimeric peptide which include the amino acids 42 to 58 of the human sequence of CD59.  
     
     
         14 . The method of  claim 11 , wherein the peptide is a covalently cyclized peptides comprising hu CD59 amino acid residues 42 to 58.  
     
     
         15 . The method of  claim 11 , wherein the composition is a peptide of less than forty amino acids residues including amino acid residues 42 to 58 of hu CD59.  
     
     
         16 . The method of  claim 10 , wherein the composition further comprises a pharmaceutically acceptable carrier for administration to patients in need thereof.  
     
     
         17 . The method of  claim 10 , wherein the patient is in need of suppression of complement-mediated inflammation.  
     
     
         18 . The method of  claim 10  wherein the compound is a peptidomimetic compound comprising the side chains of hu CD59 amino acid residues His 44 , Asn 48 , Asp 49 , Thr 51 , Thr 52 , Arg 55 , and Glu 58  in an equivalent spacial orientation and alignment to that presented on the surface of hu CD59.  
     
     
         19 . The method of  claim 18  wherein the spacial orientation and alignment of the side chains of His 44 , Asn 48 , Asp 49 , Thr 51 , Thr 52 , Arg 55 , and Glu 58  in the compound are equivalent to the spacial orientation and alignment deduced by NMR structure determination.  
     
     
         20 . A compound that specifically promotes the formation of the hu C5b-9 complex selected from the group consisting of molecules structurally mimicking C9 amino acid residues 359 to 384 when they are in a spatial orientation which promotes formation of the C5b-9 complex, wherein the compound is not hu C9.  
     
     
         21 . The compound of  claim 20 , selected from the group consisting of proteins, peptides, nucleic acids, and small molecules which bind specifically to amino acids 42 to 58 of hu CD59.  
     
     
         22 . The compound of  claim 21 , wherein the protein is an antibody.  
     
     
         23 . The compound of  claim 21 , wherein the protein is a chimeric peptide which includes the amino acids 359 to 384 of the human sequence of C9.  
     
     
         24 . The compound of  claim 21 , wherein the peptide is a covalently cyclized peptide comprising hu C9 amino acid residues 359 to 384.  
     
     
         25 . The compound of  claim 21 , wherein the composition is a peptide of less than forty amino acids residues including amino acid residues 359 to 384 of hu C9.  
     
     
         26 . The compound of  claim 20 , further comprising a pharmaceutically acceptable carrier for administration to patients in need thereof.  
     
     
         27 . A method for specifically promoting hu C5b-9 complex assembly comprising administering to a patient in need thereof an effective amount of a composition to decrease CD59 inhibition of C5b-9 complex assembly wherein the composition comprises a compound selected from the group consisting of molecules structurally mimicking C9 amino acid residues 359 to 384 when they are in a spatial orientation which promotes formation of the complex, wherein the compound is not hu C9.  
     
     
         28 . The method of  claim 27 , wherein the compound is selected from the group consisting of proteins, peptides, nucleic acids, and small molecules which bind specifically to amino acids 42 to 58 of hu CD59.  
     
     
         29 . The method of  claim 28 , wherein the protein is an antibody.  
     
     
         30 . The method of  claim 28 , wherein the protein is a chimeric peptide which include the amino acids 359 to 384 of the human sequence of C9.  
     
     
         31 . The method of  claim 28 , wherein the peptide is a covalently cyclized peptide comprising hu C9 amino acid residues 359 to 384.  
     
     
         32 . The method of  claim 28 , wherein the composition is a peptide of less than forty amino acids residues including amino acid residues 359 to 384 of hu C9.  
     
     
         33 . The method of  claim 27 , wherein the composition further comprises a pharmaceutically acceptable carrier for administration to patients in need thereof.  
     
     
         34 . The method of  claim 27 , wherein the patient is in need of complement activation.  
     
     
         35 . The method of  claim 27 , wherein the composition is administered as a adjunct to tumor therapy.