Cell-reactive, long-acting, or targeted compstatin analogs and uses thereof
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., 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 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 inhibit complement-mediated damage to a cell, tissue, or organ.
1. A compstatin analog comprising one or more clearance-reducing moieties attached to one or more compstatin analog moieties, wherein:
each compstatin analog moiety comprises a cyclic peptide having an amino acid sequence as set forth in any of SEQ ID NOs: 3-36, extended by one or more terminal amino acids at the N-terminus, C-terminus, or both, wherein the one or more amino acids has a side chain comprising a primary or secondary amine and is separated from the cyclic peptide by a rigid or flexible spacer comprising an oligo(ethylene glycol) moiety that is (—(O—CH 2 CH 2 —) n ), wherein n is between 1 and 500,
so that the compstatin analog moiety comprises the cyclic peptide, linked via its N-terminus or C-terminus to the spacer, which is linked to the one or more amino acids; and
each clearance-reducing moiety comprises a polyethylene glycol (PEG) and is covalently attached via a linking moiety to the side chain comprising a primary or a secondary amine, wherein the linking moiety comprises an unsaturated alkyl moiety, a moiety comprising a nonaromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, or an amino acid residue,
wherein the clearance-reducing moiety and the spacer are separated by the one or more amino acids comprising a side chain having a primary or secondary amine,
so that the compstatin analog comprises the cyclic peptide linked via its N-terminus or C-terminus to the spacer, which is linked to the one or more amino acids, which in turn is linked to the linking moiety and the clearance-reducing moiety.
2. A compstatin analog comprising one or more clearance-reducing moieties attached to one or more 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, 32, or 34, extended by one or more terminal amino acids at the N-terminus, C-terminus, or both; wherein the one or more amino acids has a side chain comprising a primary or secondary amine and is separated from the cyclic peptide by a rigid or flexible spacer comprising an oligo(ethylene glycol) moiety that is (—(O—CH 2 CH 2 —) n ), wherein n is between 1 and 500,
so that the compstatin analog moiety comprises the cyclic peptide, linked via its N-terminus or C-terminus to the spacer, which is linked to the one or more amino acids; and
each clearance-reducing moiety is or comprises a polyethylene glycol (PEG), the Fc domain of an immunoglobulin, an albumin moiety, or an albumin binding peptide and is covalently attached via a linking moiety to the side chain comprising a primary or a secondary amine,
wherein the linking moiety comprises an unsaturated alkyl moiety, a moiety comprising a nonaromatic cyclic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, or an amino acid residue,
wherein the clearance-reducing moiety and the spacer are separated by the one or more amino acids comprising a side chain having a primary or secondary amine,
so that the compstatin analog comprises the cyclic peptide linked via its N-terminus or C-terminus to the spacer, which is linked to the one or more amino acids, which in turn is linked to the linking moiety and the clearance-reducing moiety.
3. The compstatin analog of claim 2 , wherein the one or more terminal amino acids is or comprises a Lys.
4. The compstatin analog of claim 2 , wherein the oligo(ethylene glycol) moiety is (—(O—CH 2 —CH 2 —) n ) wherein n is between 1 and 10.
5. The compstatin analog of claim 2 , wherein 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.
6. The compstatin analog of claim 2 , wherein the spacer comprises NH 2 (CH 2 CH 2 O) n CH 2 C(═O)OH, wherein n is between 1 and 500, or an NHS ester thereof.
7. The compstatin analog of claim 6 , wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc),11-amino-3,6,9-trioxaundecanoic acid, or an NHS ester of either.
8. The compstatin analog of claim 2 , wherein the clearance reducing moiety is or comprises a PEG.
9. The compstatin analog of claim 8 wherein the PEG is a linear PEG.
10. The compstatin analog of claim 8 , wherein the PEG is a branched PEG.
11. The compstatin analog of claim 8 , wherein the compstatin analog comprises multiple PEG or modified PEG moieties.
12. The compstatin analog of claim 8 , wherein the compstatin analog comprises one or more compstatin analog moieties linked to a bifunctional PEG moiety.
13. The compstatin analog of claim 2 , wherein the compstatin analog comprises multiple compstatin analog moieties.
14. The compstatin analog of claim 13 , which is a multivalent compound comprising a plurality of compstatin analog moieties covalently linked to a polymeric backbone or scaffold.
15. The compstatin analog of claim 9 , wherein a compstatin analog moiety is attached at each end of a linear PEG.
16. The compstatin analog claim 1 , wherein the cyclic peptide has an amino acid sequence as set forth in SEQ ID NO: 28, 32, or 34.
17. The compstatin analog of claim 1 , wherein the cyclic peptide has an N-methylGly at a position corresponding to position 8 of SEQ ID NO:8.
18. The compstatin analog of claim 2 , wherein the cyclic peptide has an amino acid sequence as set forth in SEQ ID NO:28.
19. The compstatin analog of claim 2 , having a plasma half-life of at least 2 days when injected intravenously into a primate.
20. The compstatin analog of claim 19 , having a plasma half-life of at least 3 days when injected intravenously into a primate.
21. The compstatin analog of claim 20 , having a plasma half-life of at least 4 days when injected intravenously into a primate.