Compstatin and analogs thereof for eye disorders

Abstract

The present invention features the use of compstatin and complement inhibiting analogs thereof for treating and/or preventing age related macular degeneration and other conditions involving macular degeneration, choroidal neovascularization, and/or retinal neovascularization. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a second therapeutic agent. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a gel-forming material, e.g., soluble collagen, and methods of administering the compositions.

1 - 98 . (canceled) 
     
     
         99 . A composition comprising:
 (i) compstatin or a compstatin analog; and   (ii) a moiety that binds to a component present in the eye of a subject at risk of or suffering from an eye disorder characterized by macular degeneration, CNV, RNV, proliferative vitreoretinopathy, glaucoma, ocular inflammation, or any combination of these, wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), where X′aa and Xaa are selected from Trp and analogs of Trp.   
     
     
         100 . The composition of  claim 99 , wherein the moiety binds to a cellular marker present on or at the surface of an endothelial cell or retinal pigment epithelial cell. 
     
     
         101 . The composition of  claim 99 , wherein the moiety binds to a drusen constituent. 
     
     
         102 - 116 . (canceled) 
     
     
         117 . A method of producing a therapeutic agent comprising steps of:
 (i) expressing, in a recombinant host cell,
 a nucleic acid comprising:
 (a) a portion that encodes compstatin or a compstatin analog; and 
 (b) a portion that encodes a moiety that binds to a component present in the eye of a subject at risk of or suffering from an eye disorder characterized by macular degeneration, CNV, RNV, proliferative vitreoretinopathy, glaucoma, ocular inflammation, or any combination of these, 
 
 so that a polypeptide comprising compstatin or compstatin analog fused to a binding moiety is produced by the host cell; and 
   (ii) purifying the polypeptide,   wherein the compstatin analog comprises a cyclic peptide having a core sequence of X′aa Gln-Asp-Xaa-Gly (SEQ ID NO: 3), where X′aa and Xaa are selected from Trp and analogs of Trp.   
     
     
         118 . A method of testing a candidate agent for use in treatment or prevention of an eye disorder characterized by macular degeneration, choroidal neovascularization, retinal neovascularization, ocular inflammation or any combination of these, comprising steps of:
 (i) providing compstatin or a compstatin analog;   (ii) administering compstatin or compstatin analog to an animal that constitutes a model for a macular degeneration related condition, choroidal neovascularization, or retinal neovascularization; and   (iii) assessing the ability of the compstatin or compstatin analog to treat or prevent one or more features of macular degeneration, choroidal neovascularization, or retinal neovascularization.   
     
     
         119 - 126 . (canceled) 
     
     
         127 . The method of  claim 117 , further comprising a step of:
 (iii) formulating the polypeptide together with a pharmaceutically acceptable carrier.   
     
     
         128 . The method of  claim 127 , wherein the pharmaceutically acceptable carrier comprises a sterile aqueous solution, a sterile aqueous dispersion, or a sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersions. 
     
     
         129 . The method of  claim 128 , wherein the pharmaceutically acceptable carrier comprises a sterile aqueous solution. 
     
     
         130 . The method of  claim 129 , wherein the sterile aqueous solution is isotonic, pH-adjusted saline or water. 
     
     
         131 . The method of  claim 129 , wherein the sterile aqueous solution comprises benzylalkonium chloride. 
     
     
         132 . The method of  claim 117 , wherein the recombinant host cell is prokaryotic. 
     
     
         133 . The method of  claim 132 , wherein the recombinant host cell is  E. coli.    
     
     
         134 . The method of  claim 117 , wherein the recombinant host cell is eukaryotic. 
     
     
         135 . The method of  claim 134 , wherein the recombinant host cell is selected from the group consisting of a fungal cell, an insect cell, and an animal cell. 
     
     
         136 . The method of  claim 135 , wherein the recombinant host cell is an animal cell. 
     
     
         137 . The method of  claim 136 , wherein the recombinant host cell is a mammalian cell. 
     
     
         138 . The method of  claim 117 , wherein the moiety is selected from the group consisting of an antibody, an antibody fragment, and a ligand. 
     
     
         139 . The method of  claim 117 , wherein the component is a cellular marker. 
     
     
         140 . The method of  claim 139 , where in the component is a cellular marker expressed on or at the surface of a cell. 
     
     
         141 . The method of  claim 140 , wherein the cell is an endothelial cell or a retinal pigment epithelial cell. 
     
     
         142 . The method of  claim 117 , wherein the component is a drusen constituent. 
     
     
         143 . The method of  claim 142 , wherein the drusen constituent is selected from the group consisting of α1-antichymotrypsin, α1-antitrypsin, Alzheimer amyloid β peptide, advanced glycation end products, amyloid P component, apolipoprotein B, apolipoprotein E, carbohydrate moieties recognized by various lectins, cholesterol esters, clusterin, complement factors, cluster differentiation antigen, complement receptor 1, factor X, heparan sulfate proteoglycan, human leukocyte antigen DR, immunoglobulin light chains, major histocompatibility complex class II antigens, membrane cofactor protein, peroxidized lipids, phospholipids and neutral lipids, tissue inhibitor of matrix metalloproeinases-3, transthyretin, ubiquitin, and vitronectin. 
     
     
         144 . A method comprising steps of:
 (i) providing a three-dimensional structure of C3 or a portion thereof to which compstatin binds;   (ii) computationally docking a plurality of molecular structures with the structure of C3; and   (iii) selecting a molecular structure that binds to substantially the same site as that to which a compstatin or a compstatin analog binds.   
     
     
         145 . The method of  claim 144 , further comprising a step of:
 (iv) testing the ability of a test compound having the molecular structure selected in step (iii) to bind to C3.   
     
     
         146 . The method of  claim 145 , wherein step (iv) comprises contacting C3 with labeled compstatin or a labeled compstatin analog in the presence of different concentrations of the test compound. 
     
     
         147 . The method of  claim 146 , wherein the test compound is identified as a candidate compstatin mimetic if it diminishes binding of the labeled compstatin or labeled compstatin analog to C3 by at least 25%. 
     
     
         148 . The method of  claim 147 , wherein the test compound is identified as a candidate compstatin mimetic if it diminishes binding of the labeled compstatin or labeled compstatin analog to C3 by at least 50%. 
     
     
         149 . The method of  claim 99 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly-X″aa (SEQ ID NO: 4), where X′aa and Xaa are each independently selected from Trp and analogs of Trp and X″aa is selected from His, Ala, analogs of Ala, Phe, and Trp. 
     
     
         150 . The method of  claim 117 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly-X″aa (SEQ ID NO: 4), where X′aa and Xaa are each independently selected from Trp and analogs of Trp and X″aa is selected from His, Ala, analogs of Ala, Phe, and Trp.