Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods

Abstract

In some aspects, the present invention provides cell-reactive compstatin analogs and compositions comprising cell-reactive compstatin analogs. In some aspects, the invention further provides methods of using cell-reactive compstatin analogs, e.g., treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides long-acting compstatin analogs and compositions comprising long-acting compstatin analogs. In some aspects, the invention further provides methods of using long-acting compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides targeted compstatin analogs and compositions comprising targeted compstatin analogs. In some aspects, the invention further provides methods of using targeted compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ.

1 .- 175 . (canceled) 
     
     
         176 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
         is 
       
       
         
           
           
               
               
           
         
         the molecular weight of the (CH 2 CH 2 O) n  moiety is about 20 kD-100 kD. 
       
     
     
         177 . The compound of  claim 176  having the structure: 
       
         
           
           
               
               
           
         
         wherein the molecular weight of the (CH 2 CH 2 O) n  moiety is about 40,000 Daltons. 
       
     
     
         178 . The compound of  claim 176 , wherein the average molecular weight of the (CH 2 CH 2 O) n  moiety is about 40,000 Daltons. 
     
     
         179 . The compound of  claim 176 , wherein the polydispersity of the (CH 2 CH 2 O) n  moiety is 1, or between 1.005 and 1.10, or between 1.005 and 1.15, or between 1.005 and 1.20, or between 1.005 and 1.25, or between 1.005 and 1.30, or between 1.005 and 1.40, or between 1.005 and 1.50, or any value between 1.0005 and 1.50. 
     
     
         180 . A composition comprising the compound of  claim 176 , and a pharmaceutically acceptable carrier. 
     
     
         181 . A method of treating a subject in need thereof, the method comprising administering the compound of  claim 176  to the subject. 
     
     
         182 . A method of reducing the sensitivity of a cell or organ to complement-dependent damage in a subject in need thereof, the method comprising administering the compound of  claim 176  to the subject. 
     
     
         183 . A method of treating a complement-mediated disorder, the method comprising administering the compound of  claim 176  to the subject. 
     
     
         184 . A method of treating or preventing age-related macular degeneration (AMD) or geographic atrophy (GA) in a subject in need thereof, the method comprising administering the compound of  claim 176  to the subject. 
     
     
         185 . The method of  claim 184  comprising administering the compound to the eye of said subject. 
     
     
         186 . The method of  claim 185  comprising administering the compound by intravitreal administration. 
     
     
         187 . The method of  claim 183 , wherein the complement-mediated disorder is transplant rejection, ischemia/reperfusion injury, haemolytic anemia, an autoimmune disease, neuropathic pain, membranoproliferative glomerulitis, neuromyelitis optica, spinal cord injury, asthma, paroxysmal nocturnal hemoglobinuria (PNH), or chronic obstructive pulmonary disease (COPD). 
     
     
         188 . The method of  claim 181 , wherein the method comprising administering the compound by subcutaneous or intravenous administration. 
     
     
         189 . A method of making a long-acting compstatin analog, comprising reacting a compound of Formula IVa 
       
         
           
           
               
               
           
         
         with a compstatin analog moiety, wherein the compstatin analog moiety has an amino acid sequence comprising the amino acid sequence of any of SEQ ID NOs: 3-36, 37, 71, 72, 73 or 74. 
       
     
     
         190 . A method of making a long-acting compstatin analog, comprising reacting a compound of Formula B: 
       
         
           
           
               
               
           
         
         wherein T is a covalent bond or a C 1-12  straight or branched, hydrocarbon chain wherein one or more carbon units of T are optionally and independently replaced by —O—, —S—, —N(R x )—, —C(O)—, C(O)O—, OC(O)—, —N(R x )C(O)—, —C(O)N(R x )—, —S(O)—, —S(O) 2 —, —N(R x )SO 2 -, or SO 2 N(R x )—; and 
         each R x  is independently hydrogen or Ci-6 aliphatic, 
         preferably of Formula IV: 
       
       
         
           
           
               
               
           
         
         Formula IVa: 
       
       
         
           
           
               
               
           
         
         Formula V: 
       
       
         
           
           
               
               
           
         
         Formula Va: 
       
       
         
           
           
               
               
           
         
         with a compstatin analog moiety, wherein the compstatin analog moiety has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 74. 
       
     
     
         191 . The method of  claim 189 , wherein the long-acting compstatin analog comprises a clearance-reducing moiety attached to two compstatin analog moieties, wherein
 each compstatin analog moiety comprises a cyclic peptide extended by a lysine residue or a sequence comprising a lysine residue at the N-terminus, C-terminus, or both, wherein the lysine residue is separated from the cyclic portion of the peptide by a rigid or flexible spacer comprising an oligo(ethylene glycol) moiety;   the clearance reducing moiety comprises a linear polymer, wherein each end of the linear polymer is linked to one of the compstatin analog moieties by way of a carbamate;   
       wherein
 (i) the spacer comprises —(CH 2 ) m — and —(O—CH 2 —CH 2 —) n  joined covalently, wherein m is between 1 and 10 and n is between 1 and 10; and/or 
 (ii) the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid. 
 
     
     
         192 . The method of  claim 189 , wherein the long-acting compstatin analog comprises a clearance-reducing moiety attached to two compstatin analog moieties, wherein:
 each compstatin analog moiety comprises a cyclic peptide having an amino acid sequence as set forth in SEQ ID NO: 28, extended by a lysine residue or a sequence comprising a lysine residue at the N-terminus, C-terminus, or both, wherein the lysine residue is separated from the cyclic portion of the peptide by an 8-amino-3,6-dioxaoctanoic acid (AEEAc) spacer; and   the clearance reducing moiety comprises a PEG polymer having an average molecular weight of about 40 kDa, wherein each end of the polymer is linked to one of the compstatin analog moieties by way of a linker moiety that is or comprises a carbamate.   
     
     
         193 . The method of  claim 192 , wherein the long-acting compstatin analog has a structure