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US-20260125452-A1 - METHODS OF USING ACTIVIN RECEPTOR TYPE II VARIANTS

US20260125452A1US 20260125452 A1US20260125452 A1US 20260125452A1US-20260125452-A1

Abstract

The invention features methods for the treatment of a cardiovascular disease using a polypeptide containing an extracellular ActRII variant, such as an ActRIIA variant, ActRIIB variant, or ActRII chimera. The polypeptide may include an extracellular ActRII variant fused to an Fc domain monomer. Treatment of a cardiovascular disease with a polypeptide described herein may reduce fibrosis, reduce inflammation, reduce cardiac remodeling, improve cardiac function, improve ventricular function, or slow or inhibit disease progression, which may reduce or delay the need for coronary revascularization, heart valve repair or replacement, implantation of a cardioverter-defibrillator, cardiac resynchronization therapy, a ventricular assist device, or a heart transplant.

Inventors

  • Jasbir S. Seehra
  • Jennifer Lachey

Assignees

  • KEROS THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20251117

Claims (20)

  1. 1 . A method of treating a subject having or at risk of developing a calcification disease, cardiomyopathy, right-sided heart failure, left-sided heart failure, backward heart failure, forward heart failure, high-output heart failure, low-output heart failure, compensated heart failure, decompensated heart failure, a heart valve disease, an arrhythmia, hyperlipidemia, hyperlipoproteinemia, vasculitis, deep vein thrombosis, sitosterolemia, cerebrotendinous xanthomatosis, familial hypobetalipoproteinemia, aortic aneurysm, pseudoaneurysm, intramural hematoma, xanthoma, xanthelasma, hepatosteatosis, mixed dyslipidemia, hypertriglyceridemia, or ventricular dysfunction, the method comprising administering to the subject a therapeutically effective amount of: a) a polypeptide comprising an extracellular activin receptor type IIB (ActRIIB) variant, the variant having one or more amino acid substitutions relative to the sequence of GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQE CVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT (SEQ ID NO: 74), wherein the variant comprises one or more amino acid substitutions that impart reduced BMP9 binding relative to wild type extracellular ActRIIB and one or more additional amino acid substitutions, wherein the substitutions that reduce BMP9 binding comprise one or more of: i) amino acid substitution E75K; ii) amino acid substitutions Q69T and E70D; or iii) amino acid substitutions Q69D and E70T, optionally wherein the variant is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, or 7 amino acids; or b) a polypeptide comprising an extracellular activin receptor type II (ActRII) chimera, the chimera having a sequence of any one of (SEQ ID NO: 174) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 175) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 176) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 177) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 178) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 179) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 180) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 181) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 182) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 183) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 184) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 185) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 186) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 187) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 188) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 189) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 190) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 191) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 192) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 193) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, and (SEQ ID NO: 194) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, wherein X 1 is D or R, X 2 is I, F, E, D, Y, S, N, Q, or T, X 3 is N or T, X 4 is A or E, X 5 is T or K, X 6 is E or K, X 7 is E or D, X 8 is N or S, and X 9 is Q, E, K, R, D, or N, optionally wherein the chimera is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, wherein the chimera retains the two amino acids before the first cysteine.
  2. 2 - 8 . (canceled)
  3. 9 . A method of reducing inflammation, reducing cardiac remodeling, reducing fibrosis, or improving cardiac or ventricular function in a subject having or at risk of developing a calcification disease, cardiomyopathy, right-sided heart failure, left-sided heart failure, backward heart failure, forward heart failure, high-output heart failure, low-output heart failure, compensated heart failure, decompensated heart failure, a heart valve disease, an arrhythmia, ventricular dysfunction, hyperlipidemia, hyperlipoproteinemia, vasculitis, deep vein thrombosis, sitosterolemia, cerebrotendinous xanthomatosis, familial hypobetalipoproteinemia, aortic aneurysm, pseudoaneurysm, intramural hematoma, xanthoma, xanthelasma, hepatosteatosis, mixed dyslipidemia, or hypertriglyceridemia, the method comprising administering to the subject a therapeutically effective amount of: a) a polypeptide comprising an extracellular ActRIIB variant, the variant having one or more amino acid substitutions relative to the sequence of GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQE CVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT (SEQ ID NO: 74), wherein the variant comprises one or more amino acid substitutions that impart reduced BMP9 binding relative to wild type extracellular ActRIIB and one or more additional amino acid substitutions, wherein the substitutions that reduce BMP9 binding comprise one or more of: i) amino acid substitution E75K; ii) amino acid substitutions Q69T and E70D; or iii) amino acid substitutions Q69D and E70T, optionally wherein the variant is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, or 7 amino acids; or b) a polypeptide comprising an extracellular ActRII chimera, the chimera having a sequence of any one of (SEQ ID NO: 174) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 175) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 176) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 177) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 178) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 179) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 180) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 181) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 182) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 183) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 184) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 185) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 186) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 187) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 188) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 189) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 190) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 191) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 192) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 193) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, and (SEQ ID NO: 194) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, wherein X 1 is D or R, X 2 is I, F, E, D, Y, S, N, Q, or T, X 3 is N or T, X 4 is A or E, X 5 is T or K, X 6 is E or K, X 7 is E or D, X 8 is N or S, and X 9 is Q, E, K, R, D, or N, optionally wherein the chimera is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, wherein the chimera retains the two amino acids before the first cysteine.
  4. 10 - 12 . (canceled)
  5. 13 . A method of slowing or inhibiting progression of a calcification disease, cardiomyopathy, right-sided heart failure, left-sided heart failure, backward heart failure, forward heart failure, high-output heart failure, low-output heart failure, compensated heart failure, decompensated heart failure, a heart valve disease, an arrhythmia, ventricular dysfunction, hyperlipidemia, hyperlipoproteinemia, vasculitis, deep vein thrombosis, sitosterolemia, cerebrotendinous xanthomatosis, familial hypobetalipoproteinemia, aortic aneurysm, pseudoaneurysm, intramural hematoma, xanthoma, xanthelasma, hepatosteatosis, mixed dyslipidemia, or hypertriglyceridemia in a subject in need thereof or preventing or reducing aneurysm formation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of: a) a polypeptide comprising an extracellular ActRIIB variant, the variant having one or more amino acid substitutions relative to the sequence of GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQE CVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT (SEQ ID NO: 74), wherein the variant comprises one or more amino acid substitutions that impart reduced BMP9 binding relative to wild type extracellular ActRIIB and one or more additional amino acid substitutions, wherein the substitutions that reduce BMP9 binding comprise one or more of: i) amino acid substitution E75K; ii) amino acid substitutions Q69T and E70D; or iii) amino acid substitutions Q69D and E70T, optionally wherein the variant is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, or 7 amino acids; or b) a polypeptide comprising an extracellular ActRII chimera, the chimera having a sequence of any one of (SEQ ID NO: 174) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 175) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 176) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 177) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 178) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 179) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 180) GAILGRAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 181) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 182) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 183) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 184) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 185) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 186) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 187) GRGEAETRECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLDD X 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 188) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRRHCFATWKNISGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 189) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCFATWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 190) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWKNISGSIEIVKQGCWLDD X 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 191) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGSIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 192) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIEIVKQGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, (SEQ ID NO: 193) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRTDCVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, and (SEQ ID NO: 194) GAILGRSETQECIYYNANWELERTNQSGLERCEGEQX 1 KRLHCYASWRNSSGTIELVKKGCWLD DX 2 X 3 CYDRQECVX 4 X 5 X 6 X 7 X 8 PX 9 VYFCCCEGNMCNEKFSYFPEMEVTQPTS, wherein X 1 is D or R, X 2 is I, F, E, D, Y, S, N, Q, or T, X 3 is N or T, X 4 is A or E, X 5 is T or K, X 6 is E or K, X 7 is E or D, X 8 is N or S, and X 9 is Q, E, K, R, D, or N, optionally wherein the chimera is truncated from the N-terminus by deletion of 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, wherein the chimera retains the two amino acids before the first cysteine.
  6. 14 . (canceled)
  7. 15 . The method of claim 1 , wherein: a) the calcification disease is Monckeberg's vascular calcification disease, vascular calcification, or valvular calcification; b) the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular dysplasia, unclassified cardiomyopathy, pediatric cardiomyopathy, or peripartum cardiomyopathy; c) the left-sided heart failure is heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF); d) the heart failure is chronic; e) the heart failure is acute; f) the heart valve disease is aortic stenosis, mitral valve insufficiency, mitral valve prolapse, or rheumatic heart disease; g) the arrythmia is atrial flutter or atrial fibrillation, a ventricular arrythmia, cardiac arrhythmia associated with myocardial ischemia or myocardial infarction, or arrhythmia associated with cerebral hemorrhage; h) the hyperlipidemia or hyperlipoproteinemia is congenital hyperlipidemia or hyperlipoproteinemia; i) the hyperlipidemia or hyperlipoproteinemia is acquired hyperlipidemia or hyperlipoproteinemia; or j) the ventricular dysfunction is left ventricular dysfunction.
  8. 16 - 19 . (canceled)
  9. 20 . The method of claim 1 , wherein the subject: a has New York Heart Association (NYHA) Functional Class II to IV symptoms; b) has elevated N-terminal pro b-type natriuretic peptide (NT-proBNP); or c) is on a Heart Failure (HF) background therapy.
  10. 21 - 23 . (canceled)
  11. 24 . The method of claim 15 , wherein the congenital hyperlipidemia or hyperlipoproteinemia is familial combined hyperlipidemia (FCHL), primary hyperlipoproteinemia, hyperapobetalipoproteinemia, Frederickson type III hyperlipidemia (familial dysbetalipoprotenemia), Frederickson type IV hyperlipidemia (familial hypertriglyceridemia), Frederickson type V hyperlipidemia (endogenous hypertriglyceridemia), or small dense LDL syndrome (LDL phenotype B).
  12. 25 - 27 . (canceled)
  13. 28 . The method of claim 1 , wherein the method further comprises administering a HF background therapy.
  14. 29 . (canceled)
  15. 30 . The method of claim 1 , wherein the method: a) reduces fibrosis, reduces inflammation, reduces cardiac remodeling, improves cardiac function, or improves ventricular function; b) slows or inhibits progression of the disease or condition; c) delays development of or prevents the disease or condition; d) reduces, delays, or eliminates the need for coronary revascularization, heart valve repair or replacement, implantation of a cardioverter-defibrillator, cardiac resynchronization therapy, a ventricular assist device, or a heart transplant; e) reduces the risk of cardiovascular death; f) reverses progression of the disease or condition; g) decreases NT-proBNP levels; h) improves cardiopulmonary exercise testing (CPET) parameters; or i) improves echocardiographic (ECHO) parameters.
  16. 31 - 41 . (canceled)
  17. 42 . The method of claim 9 , wherein: a) the calcification disease is Monckeberg's vascular calcification disease, vascular calcification, or valvular calcification; b) the cardiomyopathy is dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular dysplasia, unclassified cardiomyopathy, pediatric cardiomyopathy, or peripartum cardiomyopathy; c) the left-sided heart failure is HFrEF or HFpEF; d) the heart failure is chronic; e) the heart failure is acute; f) the heart valve disease is aortic stenosis, mitral valve insufficiency, mitral valve prolapse, or rheumatic heart disease; g) the arrythmia is atrial flutter or atrial fibrillation, a ventricular arrythmia, cardiac arrhythmia associated with myocardial ischemia or myocardial infarction, or arrhythmia associated with cerebral hemorrhage; h) the hyperlipidemia or hyperlipoproteinemia is congenital hyperlipidemia or hyperlipoproteinemia; i) the hyperlipidemia or hyperlipoproteinemia is acquired hyperlipidemia or hyperlipoproteinemia; or j) the ventricular dysfunction is left ventricular dysfunction.
  18. 43 . The method of claim 42 , wherein the congenital hyperlipidemia or hyperlipoproteinemia is FCHL, primary hyperlipoproteinemia, hyperapobetalipoproteinemia, Frederickson type III hyperlipidemia (familial dysbetalipoprotenemia), Frederickson type IV hyperlipidemia (familial hypertriglyceridemia), Frederickson type V hyperlipidemia (endogenous hypertriglyceridemia), or small dense LDL syndrome (LDL phenotype B).
  19. 44 . The method of claim 9 , wherein the subject: a) has NYHA Functional Class II to IV symptoms; b) has elevated NT-proBNP; or c) is on a HF background therapy.
  20. 45 . The method of claim 9 , wherein the method further comprises administering a HF background therapy.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on Nov. 12, 2025, is named 51184-052007_Sequence_Listing_11_12_25.xml and is 641,657 bytes in size. BACKGROUND OF THE INVENTION Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels and are the number one cause of death globally, taking an estimated 17.9 million lives each year. Persistent inflammation and fibrosis are observed in many cardiovascular diseases, such as heart failure, and are also upregulated as part of normal aging. Failure to resolve inflammation and altered immune responses underlie the pathology of CVDs. Accordingly, therapies that reduce inflammation and fibrosis may be effective in treating or preventing the development of cardiovascular diseases. Given that cardiovascular diseases are a leading cause of death throughout the world, there remains a need for therapies that can be used to prevent or treat CVDs. SUMMARY OF THE INVENTION The present invention features polypeptides that include an extracellular activin receptor type II (ActRII) variant, such as an extracellular ActRIIA variant, an extracellular ActRIIB variant, or an extracellular ActRII chimera. In some embodiments, a polypeptide of the invention includes an extracellular ActRII variant fused to the N- or C-terminus of an Fc domain monomer (e.g., by fusion of the C-terminus of the ActRII variant to the N-terminus of an Fc domain monomer by way of a linker), which may be attached by amino acid or other covalent bonds and increase stability of the polypeptide. A polypeptide including an extracellular ActRII variant fused to an Fc domain monomer may also form a dimer (e.g., a homodimer or heterodimer) through the interaction between two Fc domain monomers. The polypeptides of the invention may be used to treat a subject having or at risk of developing a cardiovascular disease, such as cardiomyopathy, a calcification disease, heart valve disease, vasculitis, deep vein thrombosis, left-sided heart failure (e.g., heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), such as chronic HFrEF or chronic HFpEF), right-sided heart failure, backward heart failure, forward heart failure, high-output heart failure, low-output heart failure, compensated heart failure, decompensated heart failure, ventricular dysfunction (e.g., left ventricular dysfunction), an arrythmia, or an aneurysm. The polypeptides of the invention may prevent the cardiovascular disease, delay the development of the cardiovascular disease, slow the progression of the cardiovascular disease, or reduce cardiac remodeling, fibrosis, or inflammation associated with the cardiovascular disease. In some embodiments, the polypeptides of the invention reduce cardiovascular risk (e.g., in a subject being treated for another disease or condition, such as a disease or condition associated with increased risk of developing a cardiovascular disease or death due to a cardiovascular disease, such as a myelodysplastic syndrome (MDS)). Exemplary embodiments of the invention are described in the enumerated paragraphs below. E1. A method of treating a subject having a or at risk of developing a calcification disease, the method comprising administering to the subject a therapeutically effective amount of a composition of Table 10, a composition of Table 11, or a composition of Table 12.E2. A method of treating a subject having or at risk of developing cardiomyopathy, the method comprising administering to the subject a therapeutically effective amount of a composition of Table 10, a composition of Table 11, or a composition of Table 12.E3. A method of treating a subject having or at risk of developing right-sided heart failure, left-sided heart failure, backward heart failure, forward heart failure, high-output heart failure, low-output heart failure, compensated heart failure, or decompensated heart failure, the method comprising administering to the subject a therapeutically effective amount of a composition of Table 10, a composition of Table 11, or a composition of Table 12.E4. A method of treating a subject having or at risk of developing a heart valve disease, the method comprising administering to the subject a therapeutically effective amount of a composition of Table 10, a composition of Table 11, or a composition of Table 12.E5. A method of treating a subject having or at risk of developing an arrhythmia, the method comprising administering to the subject a therapeutically effective amount of a composition of Table 10, a composition of Table 11, or a composition of Table 12.E6. A method of treating a subject having or at risk of developing hyperlipidemia or hyperlipoproteinemia, the method comprising administering to the subject a therapeutically effective amount of a composition of Tab