Dosing regimens 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.

We claim: 
     
         1 . A physiologically acceptable or pharmaceutical grade composition comprising a cell-reactive compstatin analog. 
     
     
         2 . The composition of  claim 1 , wherein the composition is physiologically acceptable. 
     
     
         3 . The composition of  claim 1 , wherein the composition is a pharmaceutical grade composition. 
     
     
         4 . The composition of  claim 1 , wherein the composition is pharmaceutically acceptable for administration to a human. 
     
     
         5 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises a cell-reactive functional group capable of binding covalently to a mammalian cell. 
     
     
         6 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises a cell-reactive moiety comprising a cell-reactive functional group. 
     
     
         7 . The composition of  claim 1 , wherein the compstatin analog comprises a cell-reactive functional group that reacts with an sulfhydryl (SH) group to form a covalent bond. 
     
     
         8 . The composition of  claim 1 , wherein the compstatin analog comprises a cell-reactive functional group that reacts with an amine group to form a covalent bond. 
     
     
         9 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises a maleimide group. 
     
     
         10 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises a cell-reactive moiety, wherein the cell-reactive moiety comprises a cell-reactive functional group. 
     
     
         11 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises a cell-reactive functional group, a compstatin analog moiety, and a linking moiety that separates the cell-reactive functional group from the compstatin analog moiety portion of the cell-reactive compstatin analog. 
     
     
         12 . The composition of  claim 1 , wherein the cell-reactive compstatin analog comprises an amino acid whose side chain contains a group of formula (NH)—R, wherein R represents a moiety comprising a cell-reactive functional group. 
     
     
         13 . The composition of  claim 1 , wherein the cell-reactive 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, and wherein the compound comprises a cell-reactive moiety. 
     
     
         14 . The composition of  claim 1 , 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, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp, and wherein the compound comprises a cell-reactive moiety. 
     
     
         15 . The composition of  claim 1 , wherein the peptide has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), and X′aa1, X′aa2, X′aa3, X″aa2, X″aa3-X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin, and wherein the compound comprises a cell-reactive moiety. 
     
     
         16 . The composition of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5, are independently selected from among amino acids and amino acid analogs, wherein the peptide is cyclized via a bond between X′aa2 and X″aa4, and wherein the compound comprises a cell-reactive moiety. 
     
     
         17 . The composition of  claim 16 , wherein X′aa2 and X″aa4 are Cys, and wherein X″aa1 is optionally Ala or a single methyl unbranched amino acid, and wherein the compound comprises a cell-reactive moiety. 
     
     
         18 . The composition of  claim 16 , wherein X′aa2 and X″aa4 are Cys, wherein any one or more of X′aa1, X′aa2, X′aa3, X″aa2, X″aa3, X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin, and X″aa1 is Ala or a single methyl unbranched amino acid, and wherein the compound comprises a cell-reactive moiety. 
     
     
         19 . The composition of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence:
 Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO: 6); wherein:   Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B-Gly-Ile, and B 1  represents a first blocking moiety;   Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp;   Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;   Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and   the two Cys residues are joined by a disulfide bond, and wherein the compound comprises a cell-reactive moiety.   
     
     
         20 . The composition of  claim 19 , wherein
 Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile;
 Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; 
 Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; 
 Xaa4 is L-hr, D-hr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —NH 2 . 
   
     
     
         21 . The composition of  claim 19 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp. 
     
     
         22 . The composition of  claim 19 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components. 
     
     
         23 . The composition of  claim 19 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp. 
     
     
         24 . The composition of  claim 19 , wherein Xaa2* is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan. 
     
     
         25 . The composition of  claim 19 , wherein Xaa2* is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan and Xaa2* is Trp. 
     
     
         26 . The composition of  claim 19 , wherein the compstatin analog comprises a cyclic peptide having a sequence selected from the group consisting of: SEQ ID NOs: 9-36 and comprises a cell-reactive moiety. 
     
     
         27 . The composition of  claim 19 , wherein the compstatin analog comprises a cyclic peptide having a sequence selected from the group consisting of: SEQ ID NOs: 14, 21, 28, 29, 32, 33, 34, or 36 and comprises a cell-reactive moiety. 
     
     
         28 . The composition of  claim 19 , wherein the compstatin analog comprises a cyclic peptide having sequence of SEQ ID NO: 28, 32, or 34. 
     
     
         29 . The composition of  claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, X′aa2 and X″aa4 are not Cys, and the peptide is cyclized via a bond between X′aa2 and X″aa4, and wherein the compound comprises a cell-reactive moiety. 
     
     
         30 . The composition of  claim 29 , wherein any one or more of X′aa1, X′aa3, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in the peptide of any of  claims 18 - 28 , and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         31 . The composition of  claim 29 , wherein one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         32 . The composition of  claim 29 , wherein X′aa1, X′aa3, X″aa1, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in the cyclic peptide of any of  claims 18 - 28 , and wherein, optionally, one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         33 . The composition of any of  claims 10 - 32 , wherein the cyclic peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus. 
     
     
         34 . An isolated cell or organ having a compstatin analog covalently bonded thereto. 
     
     
         35 . The isolated cell or organ of  claim 34 , wherein the isolated cell or organ is a human cell or organ. 
     
     
         36 . The isolated cell or organ of  claim 34 , wherein the isolated cell is a blood cell or the isolated organ is a heart, kidney, liver, lung, or pancreas. 
     
     
         37 . A method of reducing the sensitivity of a cell or organ to complement-dependent damage, the method comprising contacting the cell with a cell-reactive compstatin analog, wherein the cell-reactive compstatin analog binds covalently to the cell or organ. 
     
     
         38 . The method of  claim 37 , wherein the cell or organ is a human cell or organ. 
     
     
         39 . The method of  claim 37 , wherein the cell is a blood cell or the organ is a heart, kidney, liver, lung, or pancreas. 
     
     
         40 . The method of  claim 37 , wherein the cell or organ is an isolated cell or organ to be transplanted into a subject, and the method comprises contacting the cell or organ with the cell-reactive compstatin analog prior to transplantation. 
     
     
         41 . The method of  claim 37 , wherein the cell or organ has been transplanted into a subject, and the method comprises contacting the organ with the cell-reactive compstatin analog after transplantation. 
     
     
         42 . The method of  claim 37 , wherein the method comprises perfusing the organ with a fluid comprising the cell-reactive compstatin analog. 
     
     
         43 . The method of  claim 37 , wherein the method comprises contacting the cell or organ with the cell-reactive compstatin analog during transplantation of the organ into a subject. 
     
     
         44 . The method of  claim 37 , wherein the method comprises administering the cell-reactive compstatin analog to a subject after transplantation of the cell or organ into the subject. 
     
     
         45 . The method of  claim 37 , wherein the method comprises administering the cell-reactive compstatin analog to a subject after transplantation of the organ into the subject, wherein the cell-reactive compstatin analog is administered locally to the transplanted organ. 
     
     
         46 . The method of  claim 37 , wherein the cell or organ has been or is to be transplanted into a subject who is at high risk of developing hyperacute or acute complement-mediated transfusion reaction or organ rejection. 
     
     
         47 . A method of treating a subject in need of treatment for a complement-mediated disorder, the method comprising administering a cell-reactive compstatin analog to the subject. 
     
     
         48 . The method of  claim 47 , wherein the cell-reactive compstatin analog is administered locally to a site at risk of or experiencing complement-mediated damage. 
     
     
         49 . The method of  claim 47 , wherein the disorder results in complement-mediated damage to red blood cells, and the cell-reactive compstatin analog is administered intravascularly. 
     
     
         50 . The method of  claim 47 , wherein the subject has a defect in complement regulation. 
     
     
         51 . The method of  claim 47 , wherein the subject is in need of treatment for transplant rejection. 
     
     
         52 . The method of  claim 47 , wherein the subject is in need of treatment for ischemia/reperfusion injury. 
     
     
         53 . The method of  claim 47 , wherein the subject is in need of treatment for a hemolytic anemia. 
     
     
         54 . A long-acting compstatin analog comprising one or more compstatin analog moieties and, as a clearance reducing moiety (CRM), a polymer that has a molecular weight of between 10 kilodaltons (kD) and 45 kD. 
     
     
         55 . The long-acting compstatin analog of  claim 54  comprising, as a CRM, a polymer having a molecular weight of between 20 kilodaltons (kD) and 45 kD. 
     
     
         56 . The long-acting compstatin analog of  claim 54  or  55  comprising, as a clearance-reducing moiety, a polymer having a molecular weight of 30 kilodaltons (kD). 
     
     
         57 . The long-acting compstatin analog of  claim 54  or  55  comprising, as a clearance-reducing moiety, a polymer having a molecular weight of 40 kilodaltons (kD). 
     
     
         58 . The long-acting compstatin analog of any of  claims 54 - 57 , wherein the polymer comprises polyethylene glycol (PEG). 
     
     
         59 . The long-acting compstatin analog of any of  claims 54 - 58 , wherein the polymer comprises a linear PEG. 
     
     
         60 . The long-acting compstatin analog of any of  claims 54 - 58 , wherein the polymer comprises a branched PEG. 
     
     
         61 . The long-acting compstatin analog of  claim 59 , wherein the polymer comprises a linear PEG and comprises a compstatin analog moiety attached at each end of the linear PEG. 
     
     
         62 . The long-acting compstatin analog of  claim 60 , wherein the polymer comprises a branched PEG having 3 to 10 branches. 
     
     
         63 . The long-acting compstatin analog of  claim 62 , wherein the polymer comprises a branched PEG having 3 to 10 branches and at least about 50% of said branches have a compstatin analog moiety attached thereto. 
     
     
         64 . The long-acting compstatin analog of  claim 63 , wherein the polymer comprises a branched PEG having 3 to 10 branches and at least about 75% of said branches have a compstatin analog moiety attached thereto. 
     
     
         65 . The long-acting compstatin analog of any of  claims 54 - 57 , wherein the polymer comprises human serum albumin. 
     
     
         66 . The long acting-compstatin analog of any of  claims 54 - 65  comprising between 2 and 10 compstatin analog moieties. 
     
     
         67 . The long acting-compstatin analog of any of  claims 54 - 66 , comprising between 2 and 100 compstatin analog moieties. 
     
     
         68 . The long-acting compstatin analog of any of  claims 54 - 67 , having a plasma half-life of at least 2 days when injected intravenously into a primate. 
     
     
         69 . The long-acting compstatin analog of any of  claims 54 - 68 , having a plasma half-life of at least 3 days when injected intravenously into a primate 
     
     
         70 . The long-acting compstatin analog of any of  claims 54 - 69 , having a plasma half-life of at least 4 days when injected intravenously into a primate. 
     
     
         71 . The long-acting compstatin analog of any of  claims 54 - 70 , having a molar activity of at least about 20% of the activity of a corresponding compstatin analog that has the same amino acid sequence but does not comprise said clearance reducing moiety. 
     
     
         72 . The long-acting compstatin analog of any of  claims 54 - 71 , having a molar activity of at least about 30% of the activity of a corresponding compstatin analog that does not comprise said clearance reducing moiety. 
     
     
         73 . The long-acting compstatin analog of any of  claims 54 - 72 , comprising multiple compstatin analog moieties and having a molar activity that is at least about equal to the sum of the activities of said compstatin analog moieties. 
     
     
         74 . The long-acting compstatin analog of any of  claims 54 - 73 , having a terminal half-life at least 5-fold higher than that of a corresponding compstatin analog that does not comprise said CRM at a comparable dose. 
     
     
         75 . The long-acting compstatin analog of any of  claims 54 - 74 , having a Cmax at least 10-fold higher than that of a corresponding compstatin analog that does not comprise said clearance-reducing moiety, at a comparable dose. 
     
     
         76 . The long-acting compstatin analog of any of  claims 54 - 75 , having a plasma half-life of at least 2 days when injected subcutaneously into a primate. 
     
     
         77 . The long-acting compstatin analog of  claim 76  having a plasma half-life of at least 3 days when injected subcutaneously into a primate. 
     
     
         78 . The long-acting compstatin analog of  claim 76  having a plasma half-life of at least 4 days when injected subcutaneously into a primate. 
     
     
         79 . The long-acting compstatin analog of any of  claims 76 - 78 , having a molar activity of at least about 20% of the activity of a corresponding compstatin analog that does not comprise a clearance-reducing moiety. 
     
     
         80 . The long-acting compstatin analog of any of  claims 76 - 79 , having a molar activity of at least about 30% of the activity of a compstatin analog that comprises the same amino acid sequence but does not comprise said clearance-reducing moiety. 
     
     
         81 . The long-acting compstatin analog of any of  claims 76 - 79  comprising multiple compstatin analog moieties and having a molar activity that is at least about 10% of the sum of the activities of said compstatin analog moieties. 
     
     
         82 . The long-acting compstatin analog of any of  claim 76 , having a Cmax at least 10-fold higher than that of a corresponding compstatin analog that does not comprise said clearance-reducing moiety, at a comparable dose. 
     
     
         83 . The long-acting compstatin analog of any of  claims 54 - 82 , having at least about 30% of the activity and a Cmax at least 10-fold higher than that of a corresponding compstatin analog that does not comprise said clearance-reducing moiety, at a comparable dose, and having a plasma half-life of at least 3 days. 
     
     
         84 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the compstatin analog moiety 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. 
     
     
         85 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the compstatin analog moiety 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, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp. 
     
     
         86 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the compstatin analog moiety comprises a cyclic peptide that has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), and X′aa1, X′aa2, X′aa3, X″aa2, X″aa3-X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin. 
     
     
         87 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the compstatin analog moiety comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5, are independently selected from among amino acids and amino acid analogs, wherein the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         88 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein X′aa2 and X″aa4 are Cys, and wherein X″aa1 is optionally Ala or a single methyl unbranched amino acid. 
     
     
         89 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein X′aa2 and X″aa4 are Cys, wherein any one or more of X′aa1, X′aa2, X′aa3, X″aa2, X″aa3, X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin, and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         90 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the compstatin analog moiety comprises a cyclic peptide having a sequence:
 Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO: 6); wherein:   Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B 1 -Gly-Ile, and B 1  represents a first blocking moiety;   Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp;   Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;   Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and   the two Cys residues are joined by a disulfide bond.   
     
     
         91 . The long-acting compstatin analog of  claim 90 , wherein
 Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile;
 Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; 
 Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; 
 Xaa4 is L-hr, D-hr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —NH 2 . 
   
     
     
         92 . The long-acting compstatin analog of  claim 90 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp. 
     
     
         93 . The long-acting compstatin analog of  claim 90 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components. 
     
     
         94 . The long-acting compstatin analog of  claim 90 , wherein Xaa2* is an analog of Trp having an electronegative substituent on the indole ring and not having increased hydrophobic character relative to Trp. 
     
     
         95 . The long-acting compstatin analog of  claim 90 , wherein Xaa2* is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan. 
     
     
         96 . The long-acting compstatin analog of  claim 90 , wherein Xaa2* is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan and Xaa2* is Trp. 
     
     
         97 . The long-acting compstatin analog of  claim 90  comprising a compstatin analog moiety comprising a cyclic peptide having a sequence selected from the group consisting of: SEQ ID NOs: 9-36, optionally further comprising an amino acid having a side chain comprising a primary or secondary amine or sulfhydryl-reactive group. 
     
     
         98 . The long-acting compstatin analog of  claim 90 , wherein the compstatin analog moiety comprises a cyclic peptide having a sequence selected from the group consisting of: SEQ ID NOs: 14, 21, 28, 29, 32, 33, 34, or 36. 
     
     
         99 . The long-acting compstatin analog of  claim 90 , wherein the compstatin analog moiety comprises a cyclic peptide having sequence of SEQ ID NO: 28, 32, or 34. 
     
     
         100 . The long-acting compstatin analog of any of  claims 54 - 83 , wherein the long-acting compstatin analog comprises a compstatin analog moiety comprising a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, X′aa2 and X″aa4 are not Cys, and the peptide is cyclized via a bond between X′aa2 and X″aa4. 
     
     
         101 . The long-acting compstatin analog of  claim 100 , wherein any one or more of X′aa1, X′aa3, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in the peptide of any of  claims 90 - 99 , and X″aa1 is Ala or a single methyl unbranched amino acid. 
     
     
         102 . The long-acting compstatin analog of  claim 100 , wherein one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         103 . The long-acting compstatin analog of  claim 100 , wherein X′aa1, X′aa3, X″aa1, X″aa2, X″aa3, and X″aa5 are identical to the amino acids at the corresponding positions in the cyclic peptide of any of  claims 90 - 99 , and wherein, optionally, one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a primary or secondary amine, the other one of X′aa2 and X″aa4 is an amino acid or amino acid analog having a side chain that comprises a carboxylic acid group, and the bond is an amide bond. 
     
     
         104 . The long-acting compstatin analog of any of  claims 84 - 103 , wherein the cyclic peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus. 
     
     
         105 . A long-acting compstatin analog comprising a compound that comprises (i) a cyclic peptide having a sequence selected from the group consisting of: SEQ ID NOs: 14, 21, 28, 29, 32, 33, 34, or 36; and (ii) a polymer that has a molecular weight between 10 kD and 45 kD. 
     
     
         106 . The long-acting compstatin analog of any of  claims 84 - 105  comprising a compound in which at least one NHS ester of the compound of any of Formulae I-XVI or Formulae A-H has reacted with an amino group in a side chain or terminus of a compstatin analog moiety, with the proviso that the compound of any of Formulae I-XVI or Formulae A-H has a molecular weight between 10 kD and 45 kD. 
     
     
         107 . A method of making a long-acting compstatin analog, comprising reacting the compound of any of Formulae I-XVI or Formulae A-H with a compstatin analog moiety, with the proviso that the compound of any of Formulae I-XVI or Formulae A-H has a molecular weight between 10 kD and 45 kD. 
     
     
         108 . A method of making a long-acting compstatin analog, comprising reacting the compound of any of Formulae I-XVI or Formulae A-H with a compstatin analog moiety comprising the amino acid sequence of any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40a, or 41A, with the proviso that the compound of any of Formulae I-XVI or Formulae A-H has a molecular weight between 10 kD and 45 kD. 
     
     
         109 . A long-acting compstatin analog prepared according to the method of  claim 107 - 108  or identical in structure to said long-acting compstatin analog. 
     
     
         110 . The long-acting compstatin analog of any of  claims 84 - 106  or  109  or  145 - 164 , further comprising a targeting moiety. 
     
     
         111 . A composition comprising the long-acting compstatin analog of any of  claims 54 - 105  or  109  or  145 - 164 , and a pharmaceutically acceptable carrier. 
     
     
         112 . A pharmaceutical composition comprising the long-acting compstatin analog of any of  claims 54 - 106  or  109  or  145 - 164 . 
     
     
         113 . A pharmaceutical composition comprising the long-acting compstatin analog of any of  claims 54 - 106  or  109  or  145 - 164 , and a pharmaceutically acceptable carrier. 
     
     
         114 . A method of reducing the sensitivity of a cell or organ to complement-dependent damage, the method comprising contacting the cell with a long-acting compstatin analog or composition of any of  claims 54 - 106  or  109 - 113  or  144 - 165 . 
     
     
         115 . The method of  claim 114 , wherein the cell or organ is a human cell or organ. 
     
     
         116 . The method of  claim 114 , wherein the cell is a blood cell or the organ is a heart, kidney, liver, lung, or pancreas. 
     
     
         117 . The method of  claim 114 , wherein the method comprises administering the long-acting compstatin analog or composition to a subject. 
     
     
         118 . A method of treating a subject in need of treatment for a complement-mediated disorder, the method comprising administering a long-acting compstatin analog or composition of any of  claims 54 - 106 ,  109 - 113 ,  144 - 165 , or  167 - 174  to the subject. 
     
     
         119 . The method of  claim 118  wherein the long-acting compstatin analog is administered locally to a site at risk of or experiencing complement-mediated damage. 
     
     
         120 . The method of  claim 118 , wherein the disorder results in complement-mediated damage to red blood cells. 
     
     
         121 . The method of  claim 118 , wherein the disorder results in complement-mediated damage to red blood cells, and the long-acting compstatin analog is administered intravascularly or subcutaneously. 
     
     
         122 . The method of  claim 118 , wherein the subject has a defect in complement regulation. 
     
     
         123 . The method of  claim 118 , wherein the subject is in need of treatment for transplant rejection. 
     
     
         124 . The method of  claim 118 , wherein the subject is in need of treatment for ischemia/reperfusion injury. 
     
     
         125 . The method of  claim 118 , wherein the subject is in need of treatment for a hemolytic anemia. 
     
     
         126 . The method of  claim 118 , wherein the subject is in need of treatment for an autoimmune disease. 
     
     
         127 . The method of  claim 118 , wherein the subject is in need of treatment for neuropathic pain. 
     
     
         128 . The method of  claim 118 , wherein the subject is in need of treatment for MPGN. 
     
     
         129 . The method of  claim 118 , wherein the subject is in need of treatment for neuromyelitis optica. 
     
     
         130 . The method of  claim 118 , wherein the subject is in need of treatment for spinal cord injury. 
     
     
         131 . The method of  claim 118 , wherein the subject is in need of treatment for asthma, COPD, or idiopathic pulmonary fibrosis. 
     
     
         132 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog is administered subcutaneously. 
     
     
         133 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog is administered subcutaneously one or more times daily. 
     
     
         134 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog is administered transdermally. 
     
     
         135 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog is administered subcutaneously using a pen device. 
     
     
         136 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog is administered intramuscularly. 
     
     
         137 . The method of any of  claims 118 - 131 , wherein the long-acting compstatin analog comprises a polymer having a molecular weight of about 40 kD and is administered subcutaneously one or two times per day, wherein the total daily dose is between 90 mg and 360 mg, optionally between 180 mg/day and 270 mg/day. 
     
     
         138 . The method of  claim 107  or  claim 108 , wherein the compound of any of Formulae I-XVI or Formulae A-H and the compstatin analog moiety each comprise a click functionality, and the method comprises performing a click chemistry reaction. 
     
     
         139 . A compstatin analog comprising a click chemistry group. 
     
     
         140 . The compstatin analog of  claim 139 , wherein the compstatin analog comprises a compound comprising any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         141 . The compstatin analog of  claim 139  or  claim 140 , wherein the click chemistry group comprises an azide, an alkyne, an octyne, a dibenzoaryl cyclooctyne. 
     
     
         142 . The compstatin analog of  claim 140 , wherein the click chemistry group is DBCO, DIBO, DIFO, BARAC, or BCN. 
     
     
         143 . The compstatin analog of  claim 140 , wherein the click chemistry group is suitable for a copper-free click chemistry reaction. 
     
     
         144 . A composition comprising a compstatin analog of any of  claims 139 - 143  and a CRM, wherein the CRM comprises a polymer having a molecular weight between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD. 
     
     
         145 . A conjugate formed by reaction of a compstatin analog of any of  claims 139 - 143  with a CRM comprising a complementary click chemistry group, wherein the CRM comprises a polymer having a molecular weight between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD. 
     
     
         146 . A long-acting compstatin analog comprising a compstatin analog moiety and a CRM conjugated via a click chemistry bond, wherein the CRM comprises a polymer having a molecular weight between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD. 
     
     
         147 . A long-acting compstatin analog comprising a compstatin analog moiety and a CRM, wherein the CRM comprises a POZ having a molecular weight between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD. 
     
     
         148 . A long-acting compstatin analog comprising at least two compstatin analog moieties and a CRM comprising a polymer having a molecular weight between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD, further optionally wherein each compstatin analog moiety comprises any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41 A. 
     
     
         149 . The long-acting compstatin analog of  claim 148 , wherein the long-acting compstatin analog has at least 90% of the activity, or at least 100% of the activity, on a molar basis as a compstatin analog having the same sequence as the compstatin analog moiety. 
     
     
         150 . The long-acting compstatin analog of  claim 148 , wherein the CRM comprises a PEG. 
     
     
         151 . The long-acting compstatin analog of  claim 148 , wherein the CRM comprises a POZ. 
     
     
         152 . The long-acting compstatin analog of  claim 148 , wherein the CRM comprises a polypeptide. 
     
     
         153 . The long-acting compstatin analog of any of  claims 148 - 152 , comprising two compstatin analog moieties. 
     
     
         154 . The long-acting compstatin analog of any of  claims 148 - 152 , comprising three compstatin analog moieties. 
     
     
         155 . The long-acting compstatin analog of any of  claims 148 - 152 , comprising two to eight compstatin analog moieties. 
     
     
         156 . The long-acting compstatin analog of  claim 148 , comprising two compstatin analog moieties and a linear PEG, wherein a compstatin analog moiety is linked to each end of the linear PEG, optionally via a carbamate or ester linkage. 
     
     
         157 . The long-acting compstatin analog of  claim 148 , comprising three compstatin analog moieties and a PEG. 
     
     
         158 . The long-acting compstatin analog of  claim 148 , comprising two to eight compstatin analog moieties and a PEG. 
     
     
         159 . The long-acting compstatin analog of  claim 148 , comprising two compstatin analog moieties and a POZ. 
     
     
         160 . The long-acting compstatin analog of  claim 148 , comprising three compstatin analog moieties and a POZ. 
     
     
         161 . The long-acting compstatin analog of  claim 148 , comprising two to eight compstatin analog moieties and a POZ. 
     
     
         162 . The long-acting compstatin analog of  claim 148 , comprising two compstatin analog moieties and a polypeptide. 
     
     
         163 . The long-acting compstatin analog of  claim 148 , comprising three compstatin analog moieties and a polypeptide. 
     
     
         164 . The long-acting compstatin analog of  claim 148 , comprising two to eight compstatin analog moieties and a polypeptide. 
     
     
         165 . A composition comprising a compstatin analog of any of  claims 139 - 164 , wherein the composition is optionally a pharmaceutical composition. 
     
     
         166 . The method of  claim 118 , wherein the long-acting compstatin analog is administered to treat a Th17-associated disease. 
     
     
         167 . The long-acting compstatin analog of any of  claims 54 - 106 ,  109 - 113 ,  144 - 165 , or  167 - 174 , wherein the long-acting compstatin analog has a molecular weight of at least about 30 kD, a terminal half-life of at least about 3 days when administered to a primate, and an activity on a molar basis of at least 80% of that of a compstatin analog comprising the same compstatin analog sequence as the compstatin analog moiety but not linked to the CRM. 
     
     
         168 . The long-acting compstatin analog of  claim 167 , having a molecular weight of at least at least about 40 kD. 
     
     
         169 . The long-acting compstatin analog of  claim 167  or  168 , having a terminal half-life of at least about 4 days. 
     
     
         170 . The long-acting compstatin analog of  claim 167  or  168 , having a terminal half-life of at least about 5 days. 
     
     
         171 . The long-acting compstatin analog of  claim 167  or  167 , having an activity on a molar basis of at least 90% of that of a compstatin analog comprising the same compstatin analog sequence as the compstatin analog moiety but not linked to the CRM. 
     
     
         172 . The long-acting compstatin analog of  claim 167  or  168 , having an activity on a molar basis at least equal to that of a compstatin analog comprising the same compstatin analog sequence as the compstatin analog moiety but not linked to the CRM. 
     
     
         173 . The long-acting compstatin analog of  claim 167  or  167 , wherein the compstatin analog moiety comprises any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         174 . The long-acting compstatin analog of any of  claims 167 - 173 , wherein the CRM comprises a PEG, POZ, or polypeptide. 
     
     
         175 . A method of treating a complement-mediated eye disorder comprising administering the long-acting compstatin analog of any of  claims 54 - 106 ,  109 - 113 ,  144 - 165 , or  167 - 174  to a subject in need thereof. 
     
     
         176 . The method of  claim 175 , wherein the eye disorder is AMD. 
     
     
         177 . The method of  claim 175 , wherein the eye disorder is geographic atrophy. 
     
     
         178 . The method of  claim 175 , wherein the eye disorder is intermediate AMD. 
     
     
         179 . The method of any of  claims 175 - 178 , wherein the long-acting compstatin analog is administered by intravitreal injection. 
     
     
         180 . The method of  claim 179 , wherein the LACA is administered monthly or every other month. 
     
     
         181 . The method of  claim 179  or  180 , wherein the dose administered is between 10 mg and 20 mg. 
     
     
         182 . The method of  claim 179  or  180 , wherein the dose administered is 15 mg. 
     
     
         183 . A unit dose of a LACA comprising a polymer having a molecular weight of between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD, wherein the amount of said unit dose is between 45 mg and 360 mg, optionally between 180 mg and 270 mg, e.g., 180 mg or 270 mg. 
     
     
         184 . A unit dose of a LACA for intravitreal administration, the LACA comprising a polymer having a molecular weight of between 10 kD and 45 kD, optionally between 35 kD and 45 kD, e.g., 40 kD, wherein the amount of said unit dose is between 10 mg and 20 mg, optionally 15 mg. 
     
     
         185 . The unit dose of  claim 183  or  184 , wherein the polymer has a molecular weight of about 30 kD. 
     
     
         186 . The unit dose of  claim 183  or  184 , wherein the polymer has a molecular weight of about 40 kD. 
     
     
         187 . The unit dose of any of  claims 183 - 186 , further comprising a pharmaceutically acceptable carrier. 
     
     
         188 . A syringe or container comprising the unit dose of any of  claims 183 - 187 . 
     
     
         189 . The unit dose, syringe or container of  claim 187  or  188 , wherein the LACA is present at a concentration of between 125 mg/ml and 200 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         190 . The unit dose, syringe or container of  claim 189 , wherein the LACA is present at a concentration of between 140 mg/ml and 180 mg/ml, e.g., 150 mg/ml, in the pharmaceutically acceptable carrier. 
     
     
         191 . The unit dose, syringe or container of  claim 187  or  188 , wherein the LACA is present at a concentration of between 80 mg/ml and 125 mg/ml, e.g., 100 mg/ml, in the pharmaceutically acceptable carrier. 
     
     
         192 . The unit dose, syringe, or container of any of  claims 183 - 191 , wherein the polymer is PEG. 
     
     
         193 . The unit dose, syringe, or container of any of  claims 183 - 192 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and/or an amino acid residue. 
     
     
         194 . The unit dose, syringe, or container of any of  claims 183 - 193 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via an ester or carbamate linkage. 
     
     
         195 . The unit dose, syringe, or container of any of  claims 183 - 194 , wherein the compstatin analog moiet(ies) comprise any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         196 . The unit dose, syringe, or container of any of  claims 183 - 195 , wherein a compstatin analog moiety comprises a peptide comprising a cyclic portion, which peptide is extended by one or more amino acids at the N-terminus, C-terminus, or both wherein at least one of the amino acids has a side chain that comprises a reactive functional group, wherein said one or more amino acid extension is optionally separated from the cyclic portion of the compstatin analog moiety by a spacer. 
     
     
         197 . The unit dose, syringe, or container of  claim 196 , wherein the spacer comprises a substituted or unsubstituted, saturated or unsaturated alkyl chain, or oligo(ethylene glycol) chain. 
     
     
         198 . The unit dose, syringe, or container of  claim 197 , wherein the spacer comprises an AEEAc moiety. 
     
     
         199 . The unit dose, syringe, or container of any of  claims 183 - 198 , wherein the LACA is CA28-2TS-BF or CA28-2GS-BF. 
     
     
         200 . A unit dose of a LACA comprising a polymer having a molecular weight of between 35 kD and 45 kD, wherein the amount of said unit dose is between 545 mg and 5040 mg. 
     
     
         201 . The unit dose of  claim 200 , wherein the polymer has a molecular weight of between 37.5 kD and 42.5 kD 
     
     
         202 . The unit dose of  claim 200  or  201 , wherein the polymer has a molecular weight of 40 kD. 
     
     
         203 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 545 mg and 1690 mg, optionally wherein the unit dose is for thrice weekly subcutaneous administration. 
     
     
         204 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 630 mg and 930 mg, optionally wherein the unit dose is for thrice weekly subcutaneous administration. 
     
     
         205 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 795 mg and 885 mg, optionally wherein the unit dose is for thrice weekly subcutaneous administration. 
     
     
         206 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 585 mg and 2510 mg, optionally wherein the unit dose is for twice weekly subcutaneous administration. 
     
     
         207 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 900 mg and 1395 mg, optionally wherein the unit dose is for twice weekly subcutaneous administration. 
     
     
         208 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 990 mg and 1215 mg, optionally wherein the unit dose is for twice weekly subcutaneous administration. 
     
     
         209 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 1215 mg and 1395 mg, optionally wherein the unit dose is for twice weekly subcutaneous administration 
     
     
         210 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 1080 mg and 5040 mg, optionally wherein the unit dose is for weekly subcutaneous administration. 
     
     
         211 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 2160 mg and 2520 mg, optionally wherein the unit dose is for weekly subcutaneous administration 
     
     
         212 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 2520 mg and 2880 mg, optionally wherein the unit dose is for weekly subcutaneous administration. 
     
     
         213 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 2880 mg and 3240 mg, optionally wherein the unit dose is for weekly subcutaneous administration. 
     
     
         214 . The unit dose of any of  claims 200 - 202 , wherein the amount is between 3240 mg and 3600 mg, optionally wherein the unit dose is for weekly subcutaneous administration. 
     
     
         215 . The unit dose of any of  claims 200 - 214 , further comprising a pharmaceutically acceptable carrier. 
     
     
         216 . A syringe or container comprising the unit dose of any of  claims 200 - 216 . 
     
     
         217 . The unit dose, syringe or container of any of  claims 200 - 216 , wherein the LACA is present at a concentration of between 25 mg/ml and 150 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         218 . The unit dose, syringe or container of  claim 217 , wherein the LACA is present at a concentration of between 25 mg/ml and 50 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         219 . The unit dose, syringe or container of  claim 217 , wherein the LACA is present at a concentration of between 50 mg/ml and 75 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         220 . The unit dose, syringe or container of  claim 217 , wherein the LACA is present at a concentration of between 75 mg/ml and 100 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         221 . The unit dose, syringe or container of  claim 217 , wherein the LACA is present at a concentration of between 100 mg/ml and 125 mg/ml in the pharmaceutically acceptable carrier. 
     
     
         222 . The unit dose, syringe, or container of any of  claims 200 - 221 , wherein the polymer is PEG. 
     
     
         223 . The unit dose, syringe, or container of any of  claims 200 - 222 , wherein the polymer is a linear polymer and the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and/or an amino acid residue. 
     
     
         224 . The unit dose, syringe, or container of  claim 223 , wherein one compstatin analog moiety is attached to each end of the polymer via an ester or carbamate linkage. 
     
     
         225 . The unit dose, syringe, or container of  claim 223  or  224 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a carbamate linkage. 
     
     
         226 . The unit dose, syringe, or container of any of  claims 200 - 225 , wherein the compstatin analog moiet(ies) comprise any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         227 . The unit dose, syringe, or container of any of  claims 200 - 226 , wherein a compstatin analog moiety comprises a peptide comprising a cyclic portion, which peptide is extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein said one or more amino acid extension is optionally separated from the cyclic portion of the compstatin analog moiety by a spacer. 
     
     
         228 . The unit dose, syringe, or container of  claim 227 , wherein the cyclic peptide is extended by an amino acid sequence that comprises at least one amino acid that has a side chain comprising a primary or secondary amine. 
     
     
         229 . The unit dose, syringe, or container of  claim 227  or  claim 228  at least one amino acid that has a side chain comprising a primary or secondary amine is a lysine at the C-terminus of the cyclic peptide 
     
     
         230 . The unit dose, syringe, or container of any of  claims 227 - 229 , wherein the spacer comprises a substituted or unsubstituted, saturated or unsaturated alkyl chain, or oligo(ethylene glycol) chain. 
     
     
         231 . The unit dose, syringe, or container of  claim 230 , wherein the oligo(ethylene glycol) moiety is (—(O-CH2-CH2-) n , wherein n is between 1 and 10 
     
     
         232 . The unit dose, syringe, or container of any of  claims 227 - 231 , wherein the spacer comprises —(CH2) m — and —(O-CH2-CH2-) n  joined covalently, wherein m is between 1 and 10 and n is between 1 and 10. 
     
     
         233 . The unit dose, syringe, or container of  claim 232 , wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid 
     
     
         234 . The unit dose, syringe, or container of  claim 233 , wherein the spacer comprises an AEEAc moiety. 
     
     
         235 . The unit dose, syringe, or container of any of  claims 200 - 234 , wherein the LACA is CA28-2TS-BF or CA28-2GS-BF. 
     
     
         236 . A method of inhibiting complement activation in a subject comprising administering the unit dose of any of  claims 200 - 235  to the subject subcutaneously. 
     
     
         237 . The method of  claim 236 , wherein the unit dose is administered using a syringe pump. 
     
     
         238 . The method of  claim 236 , wherein the unit dose is administered using an on-body delivery device. 
     
     
         239 . The method of any of  claims 236 - 238 , wherein the unit dose is administered in a volume of between 10 ml and 50 ml. 
     
     
         240 . The method of any of  claims 236 - 239 , wherein the unit dose is administered in a volume of between 20 ml and 40 ml. 
     
     
         241 . The method of any of  claims 236 - 240 , wherein the unit dose is administered thrice weekly. 
     
     
         242 . The method of any of  claims 236 - 240 , wherein the unit dose is administered twice weekly. 
     
     
         243 . The method of any of  claims 236 - 240 , wherein the unit dose is administered weekly. 
     
     
         244 . The method of any of  claims 236 - 243 , wherein the subject suffers from or is at risk of a complement-mediated disorder. 
     
     
         245 . A method of treating a subject in need of treatment for a complement-mediated disorder comprising administering the unit dose of any of  claims 200 - 235  to the subject subcutaneously. 
     
     
         246 . The method of  claim 245 , wherein the unit dose is administered using a syringe pump. 
     
     
         247 . The method of  claim 245 , wherein the unit dose is administered using an on-body delivery device. 
     
     
         248 . The method of any of  claims 245 - 247 , wherein the unit dose is administered in a volume of between 10 ml and 50 ml. 
     
     
         249 . The method of any of  claims 245 - 247 , wherein the unit dose is administered in a volume of between 20 ml and 40 ml, optionally wherein the volume is 20, 21, 22, 23, 24, or 25 ml. 
     
     
         250 . The method of any of  claims 245 - 249 , wherein the unit dose is administered thrice weekly. 
     
     
         251 . The method of any of  claims 245 - 249 , wherein the unit dose is administered twice weekly. 
     
     
         252 . The method of any of  claims 245 - 249 , wherein the unit dose is administered weekly. 
     
     
         253 . The method of any of  claims 244 - 252 , wherein the complement-mediated disorder is a hemolytic anemia. 
     
     
         254 . The method of any of  claims 244 - 252 , wherein the complement-mediated disorder is PNH. 
     
     
         255 . The method of any of  claims 244 - 252 , wherein the complement-mediated disorder is an autoimmune hemolytic anemia, optionally wherein the hemolytic anemia is cold agglutinin disease or warm autoimmune hemolytic anemia. 
     
     
         256 . The method of  claims 244 - 252 , wherein the complement-mediated disorder is myasthenia gravis. 
     
     
         257 . The method of  claims 244 - 252 , wherein the complement-mediated disorder is NMO. 
     
     
         258 . The method of  claims 244 - 252 , wherein the complement-mediated disorder is a polyneuropathy, or wherein the complement-mediated disorder is a nephropathy, or wherein the complement-mediated disorder is a vasculitis. 
     
     
         259 . A method of inhibiting complement activation in a subject comprising administering a LACA comprising a polymer comprising a polymer having a molecular weight of between 35 kD and 45 kD to the subject subcutaneously according to a dosing schedule in which the LACA is administered thrice weekly, twice weekly, or weekly. 
     
     
         260 . The method of  claim 259 , wherein the polymer has a molecular weight of between 37.5 kD and 42.5 kD 
     
     
         261 . The method  claim 259  or  260 , wherein the polymer has a molecular weight of 40 kD. 
     
     
         262 . The method of any of  claims 259 - 261 , wherein the LACA is administered thrice weekly in an amount between 545 mg and 1690 mg per dose. 
     
     
         263 . The method of any of  claims 259 - 261 , wherein the LACA is administered thrice weekly in an amount between 630 mg and 930 mg per dose. 
     
     
         264 . The method of any of  claims 259 - 261 , wherein the LACA is administered thrice weekly in an amount between 795 mg and 885 mg per dose. 
     
     
         265 . The method of any of  claims 259 - 261 , wherein the LACA is administered twice weekly in an amount between 585 mg and 2510 mg per dose. 
     
     
         266 . The method of any of  claims 259 - 261 , wherein the LACA is administered twice weekly in an amount between 900 mg and 1395 mg per dose. 
     
     
         267 . The method of any of  claims 259 - 261 , wherein the LACA is administered twice weekly in an amount between 990 mg and 1215 mg per dose. 
     
     
         268 . The method of any of  claims 259 - 261 , wherein the LACA is administered twice weekly in an amount between 1215 mg and 1395 mg per dose. 
     
     
         269 . The method of any of  claims 259 - 261 , wherein the LACA is administered weekly in an amount between 1080 mg and 5040 mg per dose. 
     
     
         270 . The method of any of  claims 259 - 261 , wherein the LACA is administered weekly in an amount between 2160 mg and 2520 mg per dose. 
     
     
         271 . The method of any of  claims 259 - 261 , wherein the LACA is administered weekly in an amount between 2520 mg and 2880 mg per dose. 
     
     
         272 . The method of any of  claims 259 - 261 , wherein the LACA is administered weekly in an amount between 2880 mg and 3240 mg per dose. 
     
     
         273 . The method of any of  claims 259 - 261 , wherein the LACA is administered weekly in an amount between 3240 mg and 3600 mg per dose. 
     
     
         274 . The method of any of  claims 259 - 261 , wherein the LACA is administered as a composition comprising the LACA and a pharmaceutically acceptable carrier. 
     
     
         275 . The method of any of  claims 259 - 274 , wherein the LACA is administered at a concentration of between 25 mg/ml and 150 mg/ml. 
     
     
         276 . The method of any of  claims 259 - 274 , wherein the LACA is administered at a concentration of between 25 mg/ml and 50 mg/ml, optionally between 45 mg/ml and 50 mg/ml. 
     
     
         277 . The method of any of  claims 259 - 274 , wherein the LACA is administered at a concentration of between 50 mg/ml and 75 mg/ml, optionally between 50 mg/ml and 60 mg/ml, further optionally 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mg/ml. 
     
     
         278 . The method of any of  claims 259 - 274 , wherein the LACA is administered at a concentration of between 75 mg/ml and 100 mg/ml. 
     
     
         279 . The method of any of  claims 259 - 274 , wherein the LACA is administered at a concentration of between 100 mg/ml and 125 mg/ml. 
     
     
         280 . The method of any of  claims 259 - 279 , wherein the polymer is PEG. 
     
     
         281 . The method of any of  claims 259 - 280 , wherein the polymer is a linear polymer and the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and/or an amino acid residue. 
     
     
         282 . The method of any of  claims 259 - 281 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via an ester or carbamate linkage. 
     
     
         283 . The method of any of  claims 259 - 282 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a carbamate linkage. 
     
     
         284 . The method of any of  claims 259 - 283 , wherein the compstatin analog moiet(ies) comprise any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         285 . The method of any of  claims 259 - 284 , wherein a compstatin analog moiety comprises a peptide comprising a cyclic portion, which peptide is extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein said one or more amino acid extension is optionally separated from the cyclic portion of the compstatin analog moiety by a spacer. 
     
     
         286 . The method of  claim 285 , wherein the cyclic peptide is extended by an amino acid sequence that comprises at least one amino acid that has a side chain comprising a primary or secondary amine. 
     
     
         287 . The method of  claim 285  or  286 , at least one amino acid that has a side chain comprising a primary or secondary amine is a lysine at the C-terminus of the cyclic peptide. 
     
     
         288 . The method of any of  claims 285 - 287 , wherein the spacer comprises a substituted or unsubstituted, saturated or unsaturated alkyl chain, or oligo(ethylene glycol) chain. 
     
     
         289 . The method of  claim 288 , wherein the oligo(ethylene glycol) moiety is (—(O-CH2-CH2-) n , wherein n is between 1 and 10 
     
     
         290 . The method of any of  claims 285 - 289 , wherein the spacer comprises —(CH2) m — and —(O-CH2-CH2-) n  joined covalently, wherein m is between 1 and 10 and n is between 1 and 10. 
     
     
         291 . The method of  claim 290 , wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid. 
     
     
         292 . The method of  claim 291 , wherein the spacer comprises an AEEAc moiety. 
     
     
         293 . The method of any of  claims 259 - 292 , wherein the LACA is CA28-2TS-BF or CA28-2GS-BF. 
     
     
         294 . The method of any of  claims 259 - 293 , wherein the subject suffers from a complement-mediated disorder. 
     
     
         295 . A method of treating a subject in need of treatment of a complement-mediated disorder comprising administering a LACA comprising a polymer comprising a polymer having a molecular weight of between 35 kD and 45 kD to the subject subcutaneously according to a dosing schedule in which the LACA is administered thrice weekly, twice weekly, or weekly. 
     
     
         296 . The method of  claim 295 , wherein the polymer has a molecular weight of between 37.5 kD and 42.5 kD 
     
     
         297 . The method  claim 295  or  296 , wherein the polymer has a molecular weight of 40 kD. 
     
     
         298 . The method of any of  claims 295 - 297 , wherein the LACA is administered thrice weekly in an amount between 545 mg and 1690 mg per dose. 
     
     
         299 . The method of any of  claims 295 - 297 , wherein the LACA is administered thrice weekly in an amount between 630 mg and 930 mg per dose. 
     
     
         300 . The method of any of  claims 295 - 297 , wherein the LACA is administered thrice weekly in an amount between 795 mg and 885 mg per dose. 
     
     
         301 . The method of any of  claims 295 - 297 , wherein the LACA is administered twice weekly in an amount between 585 mg and 2510 mg per dose. 
     
     
         302 . The method of any of  claims 295 - 297 , wherein the LACA is administered twice weekly in an amount between 900 mg and 1395 mg per dose. 
     
     
         303 . The method of any of  claims 295 - 297 , wherein the LACA is administered twice weekly in an amount between 990 mg and 1215 mg per dose, optionally wherein the amount is at least 1044 mg, 1056 mg, 1060 mg, 1078 mg, 1080 mg, 1100 mg, 1104 mg, 1120 mg, 1122 mg, 1125 mg, 1140 mg, 1144 mg, 1150 mg, or 1170 mg. 
     
     
         304 . The method of any of  claims 295 - 297 , wherein the LACA is administered twice weekly in an amount between 1215 mg and 1395 mg per dose. 
     
     
         305 . The method of any of  claims 295 - 297 , wherein the LACA is administered weekly in an amount between 1080 mg and 5040 mg per dose. 
     
     
         306 . The method of any of  claims 295 - 297 , wherein the LACA is administered weekly in an amount between 2160 mg and 2520 mg per dose. 
     
     
         307 . The method of any of  claims 295 - 297 , wherein the LACA is administered weekly in an amount between 2520 mg and 2880 mg per dose. 
     
     
         308 . The method of any of  claims 295 - 297 , wherein the LACA is administered weekly in an amount between 2880 mg and 3240 mg per dose. 
     
     
         309 . The method of any of  claims 295 - 297 , wherein the LACA is administered weekly in an amount between 3240 mg and 3600 mg per dose. 
     
     
         310 . The method of any of  claims 295 - 297 , wherein the LACA is administered as a composition comprising the LACA and a pharmaceutically acceptable carrier. 
     
     
         311 . The method of any of  claims 295 - 310 , wherein the LACA is administered at a concentration of between 25 mg/ml and 150 mg/ml. 
     
     
         312 . The method of any of  claims 295 - 310 , wherein the LACA is administered at a concentration of between 25 mg/ml and 50 mg/ml, optionally wherein (a) the concentration is 45, 46, 47, 48, 49, or 50 mg/ml; (b) the LACA is administered twice weekly in an amount between 990 mg and 1215 mg per dose, optionally wherein the amount is between 1056 mg and 1200 mg LACA per dose, e.g. 1056 mg, 1078 mg, 1080 mg, 1100 mg, 1104 mg, 1125 mg, 1140 mg, 1150, or 1170 mg per dose; (c) each dose is administered in a volume between 22 ml and 25 ml and the concentration of LACA is between 45 mg/ml and 50 mg/ml; (d) 22 ml of a composition comprising 49 mg/ml LACA is administered SC twice a week; (e) 23 ml of a composition comprising 48 mg/ml LACA is administered SC twice a week; (f) 24 ml of a composition comprising 45 mg/ml LACA is administered SC twice a week; (g) 24 ml of a composition comprising 46 mg/ml LACA is administered SC twice a week; (h) 25 ml of a composition comprising 44 mg/ml LACA is administered SC twice a week; and/or (i) 25 ml of a composition comprising 45 mg/ml LACA is administered SC twice a week; (j) 25 ml of a composition comprising 46 mg/ml LACA is administered SC twice a week; and/or (k) 26 ml of a composition comprising 45 mg/ml LACA is administered SC twice a week. 
     
     
         313 . The method of any of  claims 295 - 310 , wherein the LACA is administered at a concentration of between 50 mg/ml and 75 mg/ml, optionally wherein (a) the concentration is 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mg/ml; (b) the LACA is administered twice weekly in an amount between 990 mg and 1215 mg per dose, optionally wherein the amount is between 1044 mg and 1200 mg LACA per dose, e.g. 1044 mg, 1060 mg, 1080 mg, 1120 mg, 1122 mg, 1125 mg, 1140 mg, or 1144 mg per dose; (c) each dose is administered in a volume between 18 ml and 25 ml and the concentration of LACA is between 50 mg/ml and 60 mg/ml; (d) 18 ml of a composition comprising 58 mg/ml LACA is administered SC twice a week; (e) 18 ml of a composition comprising 60 mg/ml LACA is administered SC twice a week; (f) 18 ml of a composition comprising 60 mg/ml LACA is administered SC twice a week; (g) 20 ml of a composition comprising 54 mg/ml LACA is administered SC twice a week; (h) 20 ml of a composition comprising 55 mg/ml LACA is administered SC twice a week; (i) 20 ml of a composition comprising 56 mg/ml LACA is administered SC twice a week; ( ) 22 ml of a composition comprising 50 mg/ml LACA is administered SC twice a week; (k) 22 ml of a composition comprising 51 mg/ml LACA is administered SC twice a week; (1) 22 ml of a composition comprising 52 mg/ml LACA is administered SC twice a week. 
     
     
         314 . The method of any of  claims 295 - 310 , wherein the LACA is administered at a concentration of between 75 mg/ml and 100 mg/ml. 
     
     
         315 . The method of any of  claims 295 - 310 , wherein the LACA is administered at a concentration of between 100 mg/ml and 125 mg/ml. 
     
     
         316 . The method of any of  claims 295 - 315 , wherein the polymer is PEG. 
     
     
         317 . The method of any of  claims 295 - 316 , wherein the polymer is a linear polymer and the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and/or an amino acid residue. 
     
     
         318 . The method of any of  claims 295 - 317 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via an ester or carbamate linkage. 
     
     
         319 . The method of any of  claims 295 - 318 , wherein the LACA comprises two compstatin analog moieties, wherein one compstatin analog moiety is attached to each end of the polymer via a carbamate linkage. 
     
     
         320 . The method of any of  claims 295 - 319 , wherein the compstatin analog moiet(ies) comprise any of SEQ ID NOs: 3-36, 37, 37A, 38A, 39A, 40A, or 41A. 
     
     
         321 . The method of any of  claims 295 - 320 , wherein a compstatin analog moiety comprises a peptide comprising a cyclic portion, which peptide is extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein said one or more amino acid extension is optionally separated from the cyclic portion of the compstatin analog moiety by a spacer. 
     
     
         322 . The method of  claim 321 , wherein the cyclic peptide is extended by an amino acid sequence that comprises at least one amino acid that has a side chain comprising a primary or secondary amine. 
     
     
         323 . The method of  claim 321  or  322 , at least one amino acid that has a side chain comprising a primary or secondary amine is a lysine at the C-terminus of the cyclic peptide. 
     
     
         324 . The method of any of  claims 321 - 333 , wherein the spacer comprises a substituted or unsubstituted, saturated or unsaturated alkyl chain, or oligo(ethylene glycol) chain. 
     
     
         325 . The method of  claim 324 , wherein the oligo(ethylene glycol) moiety is (—(O-CH2-CH2-) n , wherein n is between 1 and 10 
     
     
         326 . The method of any of  claims 321 - 325 , wherein the spacer comprises —(CH2) m — and —(O-CH2-CH2-) n  joined covalently, wherein m is between 1 and 10 and n is between 1 and 10. 
     
     
         327 . The method of  claim 326 , wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid. 
     
     
         328 . The method of  claim 327 , wherein the spacer comprises an AEEAc moiety. 
     
     
         329 . The method of any of  claims 295 - 328 , wherein the LACA is CA28-2TS-BF or CA28-2GS-BF. 
     
     
         330 . The method of any of  claims 294 - 329 , wherein the complement-mediated disorder is a hemolytic anemia. 
     
     
         331 . The method of any of  claims 294 - 329 , wherein the complement-mediated disorder is PNH. 
     
     
         332 . The method of any of  claims 294 - 329 , wherein the complement-mediated disorder is an autoimmune hemolytic anemia, optionally wherein the hemolytic anemia is cold agglutinin disease or warm autoimmune hemolytic anemia. 
     
     
         333 . The method of  claims 294 - 329 , wherein the complement-mediated disorder is myasthenia gravis. 
     
     
         334 . The method of  claims 294 - 329 , wherein the complement-mediated disorder is NMO. 
     
     
         335 . The method of  claims 294 - 329 , wherein the complement-mediated disorder is a polyneuropathy, or wherein the complement-mediated disorder is a nephropathy, or wherein the complement-mediated disorder is a vasculitis. 
     
     
         336 . The unit dose, syringe, container, or method of any of  claims 183 - 335 , wherein the compstatin analog moiet(ies) comprise SEQ ID NO: 28. 
     
     
         337 . The unit dose, syringe, container, or method of any of  claims 175 - 336 , wherein the long-acting compstatin analog is in a composition comprising one or more excipients selected from the group consisting of sugar alcohols and non-reducing sugars. 
     
     
         338 . The unit dose, syringe, container, or method of  claim 337 , wherein the excipient is trehalose or sorbitol. 
     
     
         339 . The unit dose, syringe, container, or method of  claim 337  or  claim 338 , wherein the composition has a pH of between 4.8 and 5.2. 
     
     
         340 . The unit dose, syringe, container, or method of any of  claims 337 - 340 , wherein the composition comprises sodium acetate as a buffer substance. 
     
     
         341 . The unit dose, syringe, container, or method of any of  claims 337 - 340 , wherein the composition has an osmolality between 250 mOsm and 380 mOsm, optionally wherein the osmolality is between 280 mOsm and 350 mOsm. 
     
     
         342 . A composition comprising about 150 mg/ml CA28-2GS-BF or CA28-2TS-BF and between 0.50% and 0.55% NaCl in water. 
     
     
         343 . The composition of  claim 342 , wherein the concentration of NaCl is between 0.51%, and 0.54% NaCl, optionally between 0.52% NaCl and 0.53% NaCl. 
     
     
         344 . A composition comprising about 150 mg/ml CA28-2GS-BF or CA28-2TS-BF and between 3.0% and 3.6% sorbitol. 
     
     
         345 . The composition of  claim 344 , wherein the concentration of sorbitol is 3.1%, 3.2%, 3.3%, 3.4%, or 3.5%. 
     
     
         346 . A composition comprising about 150 mg/ml CA28-2GS-BF or CA28-2TS-BF and trehalose. 
     
     
         347 . The composition of  claim 346 , wherein the concentration of trehalose is between 6.6% and 7.0%, optionally 6.7%, 6.8%, or 6.9%. 
     
     
         348 . The composition of any of  claims 342 - 347 , wherein the concentration of CA28-2GS-BF or CA28-2TS-BF is between 145 mg/ml and 155 mg/ml, optionally 150 mg/ml, 
     
     
         349 . The composition of any of  claims 342 - 348 , wherein the composition comprises about 20 mM sodium acetate. 
     
     
         350 . The composition of any of  claims 342 - 349 , in a volume of about 100 microliters. 
     
     
         351 . The composition of any of  claims 342 - 349 , for intravitreal administration. 
     
     
         352 . The composition of any of  claims 342 - 351 , for use in treating an eye disorder, optionally wherein the eye disorder is age-related macular degeneration. 
     
     
         353 . The composition of  claim 352 , wherein the eye disorder is AMD characterized by geographic atrophy. 
     
     
         354 . A composition comprising CA28-2GS-BF or CA28-2TS-BF and sorbitol. 
     
     
         355 . The composition of  claim 354 , wherein the concentration of CA28-2GS-BF or CA28-2TS-BF about 55 mg/ml, optionally between 52 and 57 mg/ml. 
     
     
         356 . The composition of  claim 355 , wherein the concentration of CA28-2GS-BF or CA28-2TS-BF is 53 mg/ml, 54 mg/ml, or 55 mg/ml 
     
     
         357 . The composition of any of  claims 354 - 356 , for subcutaneous administration. 
     
     
         358 . The composition of any of  claims 354 - 357 , for use in treating a complement-mediated disorder. 
     
     
         359 . The composition of  claim 358 , wherein the disorder results in complement-mediated damage to red blood cells, optionally wherein the disorder is PNH or AIHA. 
     
     
         360 . The composition of  claim 359 , wherein the disorder is neuromyelitis optica, myasthenia gravis, or nephropathy. 
     
     
         361 . The composition of any of  claims 342 - 360 , wherein the pH of the composition is between 4.8 and 5.2, optionally wherein the pH of the composition is 5.0.