Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods
In some aspects, the present invention provides compositions and methods of treatment comprising long-acting compstatin analogs. In some aspects, long-acting compstatin analogs comprise a clearance-reducing moiety attached to two compstatin analog moieties, wherein each compstatin analog moiety comprises a cyclic peptide comprising the 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 a spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc) moiety, the clearance reducing moiety comprises a polymer, 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, and wherein the polymer is a PEG having an average molecular weight of about 40 kDa.
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 having an amino acid sequence as set form 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.
2. The long-acting compstatin analog of claim 1 , having a structure
3. A method of treating a complement-mediated disorder in a subject, the method comprising administering to the subject a composition comprising a long-acting compstatin analog, 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 form 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.
4. The method of claim 3 , wherein the administering step comprises administration of the long-acting compstatin analog through a parenteral route of administration.
5. The method of claim 4 , wherein the route of administration is subcutaneous, intravenous, intravitreal, or intramuscular.
6. The method of claim 3 , wherein the complement-mediated disorder is age-related macular degeneration.
7. The method of claim 3 , wherein the long-acting compstatin analog has a structure
8. The long-acting compstatin analog of claim 1 , having a structure as is produced when first and second compstatin analogs of SEQ ID NO:28, incorporating an AEEAc-Lys moiety C-terminal to the Thr residue of SEQ ID NO:28, are each conjugated with an NETS-ester-activated PEG with molecular weight of 40 kD.
9. The long-acting compstatin analog of claim 8 , wherein the NETS-ester-activated PEG is a carbonate-ester-activated PEG.