Claims for Patent: 11,661,441

Summary for Patent: 11,661,441

Title:	Cell-reactive, long-acting, or targeted compstatin analogs and uses thereof
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., 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.
Inventor(s):	Cedric Francois, Pascal Deschatelets
Assignee:	Apellis Pharmaceuticals Inc
Application Number:	US17/204,742
Patent Claims:	1. A method of treating a subject in need of treatment for a complement-mediated disorder, the method comprising administering a long-acting compstatin analog to the subject, wherein the long-acting compstatin analog comprises 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—CH2CH2—)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. The method of claim 1, wherein the disorder results in complement-mediated damage to red blood cells. 3. The method of claim 2, wherein the complement-mediated disorder is Paroxysmal Nocturnal Hemoglobinuria (PNH). 4. The method of claim 3, wherein the long-acting compstatin analog is administered intravascularly or subcutaneously. 5. The method of claim 1, wherein the step of administering comprises administering one or more doses of the long-acting compstatin analog. 6. The method of claim 5, wherein each dose comprises between 5 mg/kg to 20 mg/kg of the long-acting compstatin analog. 7. The method of claim 1, wherein the subject is transfusion-dependent. 8. A method of making the long-acting compstatin analog of claim 1, comprising reacting the compound of any of Formulae I-XVI or Formulae A-H with a compstatin analog moiety comprising a cyclic peptide, wherein the amino acid sequence of the cyclic peptide is SEQ ID NO: 3-36: wherein the reactive functional group is selected from the group consisting of sulfates, imidates, ortho esters, sulfites, carbamates and N-hydroxysuccinimide esters. 9. A long-acting compstatin analog comprising one or more clearance reducing moieties attached to one or more compstatin analog moieties, wherein: (a) each compstatin analog moiety comprises a cyclic peptide extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein the cyclic peptide comprises the amino acid sequence of SEQ ID NO: 8 having 2, 3, or 4 substitutions, wherein the cyclic peptide: (i) has a tryptophan analog selected from the group consisting of 2-naphthylalanine (2-NaI), 1-naphthylalanine (1-NaI), 2-indanylglycine carboxylic acid (Ig1), dihydrotrpytophan (Dht), 4-benzoyl-L-phenylalanine, β-3-benzothienyl-L-alanine, 1-methyltryptophan, and 5-methyltryptophan at position 4 relative to SEQ ID NO:8; (ii) has a tryptophan or 5-fluorotryptophan at position 7 relative to SEQ ID NO:8; and (ii) has an alanine or 2-aminobutyric acid (2-Abu) at position 9 relative to SEQ ID NO:8; and wherein the one or more amino acids has a side chain comprising a primary or secondary amine and is separated from the cyclic portion of the peptide by a rigid or flexible spacer comprising an oligo(ethylene glycol) moiety; and (b) each clearance reducing moiety comprises a PEG. 10. The long-acting compstatin analog of claim 9, wherein the one or more amino acids comprise a Lys residue. 11. The long-acting compstatin analog of claim 9, wherein the oligo(ethylene glycol) moiety is (—(O—CH2—CH2—)n, wherein n is between 1 and 10. 12. The long-acting compstatin analog of claim 9, 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. 13. The long-acting compstatin analog of claim 9, wherein the spacer comprises 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid. 14. The long-acting compstatin analog of claim 9, comprising a clearance-reducing moiety having a molecular weight of at least about 5 kilodaltons (kD). 15. The long-acting compstatin analog of claim 9, comprising a clearance-reducing moiety having a molecular weight of at least about 10 kD. 16. The long-acting compstatin analog of claim 9, wherein the one or more clearance reducing moieties are attached directly or via a linking moiety to the one or more compstatin analog moieties. 17. The long-acting compstatin analog of claim 9, wherein the one or more clearance reducing moieties are attached via a linking moiety to the one or more compstatin analog moieties, and 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, and/or an amino acid residue. 18. The long-acting compstatin analog of claim 9, comprising a clearance-reducing moiety having a molecular weight of between about 20 kD and about 100 kD. 19. The long-acting compstatin analog of claim 9, comprising a clearance-reducing moiety having a molecular weight of at least about 40 kilodaltons (kD). 20. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a linear PEG. 21. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a branched PEG. 22. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a linear PEG and the compstatin analog moiety is attached at each end of the linear PEG. 23. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a branched PEG having 3 to 10 branches. 24. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a branched PEG having 3 to 10 branches and at least 50% of said branches have a compstatin analog moiety attached thereto. 25. The long-acting compstatin analog of claim 9, wherein the clearance reducing moiety comprises a branched PEG having 3 to 10 branches and at least 75% of said branches have a compstatin analog moiety attached thereto. 26. The long acting-compstatin analog of claim 9, comprising between 2 and 10 compstatin analog moieties. 27. The long acting-compstatin analog of claim 9, comprising between 2 and 100 compstatin analog moieties. 28. The long-acting compstatin analog of claim 9, having a plasma half-life of at least 2 days when injected intravenously into a primate. 29. The long-acting compstatin analog of claim 9, having a plasma half-life of at least 3 days when injected intravenously into a primate. 30. The long-acting compstatin analog of claim 9, having a plasma half-life of at least 4 days when injected intravenously into a primate. 31. The long-acting compstatin analog of claim 9, comprising a clearance reducing moiety and having a molar activity of at least 20% of the activity of a corresponding compstatin analog that has the same amino acid sequence but does not comprise said clearance reducing moiety. 32. The long-acting compstatin analog of claim 9, comprising a clearance reducing moiety and having a molar activity of at least 30% of the activity of a corresponding compstatin analog that does not comprise said clearance reducing moiety. 33. The long-acting compstatin analog of claim 9, comprising multiple compstatin analog moieties and having a molar activity that is at least 10% of the sum of the activities of said compstatin analog moieties. 34. The long-acting compstatin analog of claim 9, comprising a clearance reducing moiety and having a terminal half-life at least 5-fold higher than that of a corresponding compstatin analog that does not comprise said clearance-reducing moiety at a comparable dose.