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

1. A long-acting compstatin analog comprising 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 —(CH2) m — and —(O—CH2—CH2—) 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.

2. The long-acting compstatin analog of claim 1 , wherein the cyclic peptide comprises an amino acid sequence as set forth in any of SEQ ID NOs: 3-36, 71, 72, 73, or 74.

3. The long-acting compstatin analog of claim 1 , 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.

4. The long-acting compstatin analog of claim 3 , wherein m is 1 and n is 2.

5. The long-acting compstatin analog of claim 1 , wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid.

6. The long-acting compstatin analog of claim 1 , wherein the linear polymer is polyethylene glycol (PEG) or polyoxazoline (POZ).

7. The long-acting compstatin analog of claim 6 , wherein the linear polymer is PEG.

8. The long-acting compstatin analog of claim 7 , wherein the PEG has an average molecular weight of about 40 kD.

9. The long-acting compstatin analog of claim 1 , having a terminal half-life of at least about 3 days when administered to a primate.

10. The long-acting compstatin analog of claim 9 , having a terminal half-life of at least about 5 days when administered to a primate.

11. The long-acting compstatin analog of claim 1 , 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 clearance-reducing moiety.

12. The long-acting compstatin analog of claim 2 , wherein the cyclic peptide comprises an amino acid sequence as set forth in SEQ ID NO: 28.