Claims for Patent: 10,208,089

Summary for Patent: 10,208,089

Title:	Modulation of complement activity
Abstract:	The present invention provides modulators of complement activity. Also provided are methods of utilizing such modulators as therapeutics.
Inventor(s):	Hoarty Michelle Denise, Dhamnaskar Ketki Ashok, Elbaum Daniel, Josephson Kristopher, Larson Kelley Cronin, Ma Zhong, Nims Nathan Ezekiel, Ricardo Alonso, Seyb Kathleen, Tang Guo-Qing, Treco Douglas A., Wang Zhaolin, Ye Ping, Zheng Hong, Perlmutter Sarah Jacqueline, Hammer Robert Paul
Assignee:	Ra Pharmaceuticals, Inc.
Application Number:	US16128561
Patent Claims:	1. A polypeptide of the formula R1-Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-R , wherein:{'sub': '1', 'Ris selected from the group consisting of an acetyl group, H, an acyl group, a heptanoyl group, an amide, a carbamate, urea, polyethylene glycol (PEG), hydroxyalkyl starch and chloroacetic acid, or is absent;'}Xaa0 is absent or Met;Xaa1 is selected from the group consisting of Cys, Lys, (S)-2-amino-5-azidopentanoic acid, and 3-thiopropionic acid, or is absent;Xaa2 is selected from the group consisting of Val, Ala, and D-Ala, or is absent;Xaa3 is selected from the group consisting of Glu, norvaline, and Ala, or is absent;Xaa4 is selected from the group consisting of Arg, Cys, Ala, Ser, and norvaline, or is absent;Xaa5 is selected from the group consisting of Phe, Tyr, N-methyl-tyrosine, and Ala, or is absent;Xaa6 is selected from the group consisting of Cys, Glu, N-methyl-glutamic acid, Asp, (S)-2-aminopent-4-ynoic acid, and Ala;Xaa7 is selected from the group consisting of Asp, Asn, N-methyl-asparagine, alpha-methyl L-aspartic acid, (S)-2-amino-3-(1H-tetrazol-5-yl)propanoic acid, N-methyl-aspartic acid, cycloleucine, 4-amino-tetrahydro-pyran-4-carboxylic acid, and Ala;Xaa8 is selected from the group consisting of tert-butylglycine, Val and Ala;Xaa9 is Tyr;Xaa10 is selected from the group consisting of 7-azatryptophan, Trp, 3-aminomethyl-L-phenyalanine, N-methyl-tryptophan, and 1-methyl-tryptophan;Xaa11 is Glu;Xaa12 is Tyr;Xaa13 is Pro;Xaa14 is selected from the group consisting of cyclohexylglycine, phenylglycine, D-phenylglycine, N-methyl-phenylglycine, amino isobutyric acid, and Ala, or is absent;Xaa15 is selected from the group consisting of norvaline, Lys, and Pro, or is absent;Xaa16 is absent or selected from the group consisting of N-ε-palmitoyl lysine, N-ε-lauryl lysine, N-ε-capryl lysine, N-ε-caprylic lysine, B20, B28, K14, Cys, and Lys; and{'sub': 2', '2, 'Ris —NHor is absent.'}2. The polypeptide of claim 1 , further comprising a bridging moiety between two amino acids.4. The polypeptide of claim 2 , wherein the bridging moiety comprises a feature selected from the group consisting of a disulfide bond claim 2 , an amide bond (lactam) claim 2 , a thioether bond an aromatic ring claim 2 , an unsaturated aliphatic hydrocarbon chain claim 2 , a saturated aliphatic hydrocarbon chain and a triazole ring.5. The polypeptide of any of claim 1 , wherein the peptide comprises a cyclic loop claim 1 , wherein the cyclic loop is of a length selected from the group consisting of 1 amino acid claim 1 , 2 amino acids claim 1 , 3 amino acids claim 1 , 4 amino acids claim 1 , 5 amino acids claim 1 , 6 amino acids claim 1 , 7 amino acids claim 1 , 8 amino acids claim 1 , 9 claim 1 , amino acids claim 1 , 10 amino acids claim 1 , 11 amino acids claim 1 , 12 amino acids claim 1 , 13 amino acids claim 1 , 14 amino acids claim 1 , 15 amino acids and 16 amino acids.6. The polypeptide of claim 2 , wherein residue Xaa1 is cysteine and wherein the bridging moiety joins residue Xaa1 and Xaa6.7. The polypeptide of claim 4 , wherein said feature comprises an aromatic ring and wherein said bridging moiety is formed by reaction with a poly(bromomethyl)benzene.8. The polypeptide of claim 7 , wherein the poly(bromomethyl)benzene is selected from the group consisting of 1 claim 7 ,2-bis(bromomethyl)benzene claim 7 , 1 claim 7 ,3-bis(bromomethyl)benzene and 1 claim 7 ,4-bis(bromomethyl)benzene.9. The polypeptide of wherein the reagent is 1 claim 8 ,3-bis(bromomethyl)benzene.10. The polypeptide of claim 4 , wherein said feature comprises a disulfide bond between two cysteine residues.11. The polypeptide of claim 4 , wherein said feature comprises an aromatic ring and wherein said bridging moiety is produced by reaction with a compound selected from the group consisting of 2 claim 4 ,6-bis(bromomethyl)pyridine claim 4 , (E)-1 claim 4 ,4-dibromobut-2-ene and 1 claim 4 ,2-bis(bromomethyl)-4-alkylbenzene.12. The polypeptide of claim 1 , wherein said polypeptide is conjugated to a hydrophilic polymer.13. The polypeptide of claim 12 , wherein the hydrophilic polymer is selected from the group consisting of polyalkylene oxide homopolymers claim 12 , polypropylene glycols claim 12 , polyoxyethylenated polyols and copolymers thereof.14. The polypeptide of claim 12 , wherein the hydrophilic polymer comprises polyethylene glycol (PEG).15. The polypeptide of comprising a polypeptide-PEG conjugate.16. The polypeptide of comprising at least one lipid moiety.17. The polypeptide of claim 1 , wherein said polypeptide is conjugated to an albumin-binding polypeptide claim 1 , wherein the albumin-binding polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 202-204.18. The polypeptide of claim 1 , wherein said polypeptide is conjugated to a cell penetrating polypeptide claim 1 , wherein the cell penetrating polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 205-210.19. A method for treating a complement-related disease claim 1 , disorder claim 1 , or condition in a subject claim 1 , the method comprising administering the polypeptide of claim 1 , wherein the polypeptide inhibits C5 cleavage.20. The method of claim 19 , wherein the complement-related disease claim 19 , disorder claim 19 , or condition comprises hemolysis.21. The method of claim 20 , wherein the hemolysis is caused by thrombin-induced complement activation.