Activin receptor type II chimeras and methods of use thereof
Inventors
Seehra, Jasbir S. • Lachey, Jennifer • TSENG, Claire • O'NEILL, Jason • Thøgersen, Henning
Assignees
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Publication Number
US-12522646-B2
Publication Date
2026-01-13
Expiration Date
Abstract
The invention features polypeptides that include an extracellular ActRII chimera. In some embodiments, a polypeptide of the invention includes an extracellular ActRII chimera fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), low platelet levels (e.g., thrombocytopenia), low neutrophil levels (e.g., neutropenia), fibrosis, metabolic disorders, and/or pulmonary hypertension.
Core Innovation
The invention relates to extracellular activin receptor type II (ActRII) chimeric polypeptides defined by sequence variants (SEQ ID NO: 1 through SEQ ID NO: 21) with allowed substitutions at positions X1-X9 and optional N-terminal truncation by deletion of 1-9 amino acids while retaining the two amino acids before the first cysteine. The chimera can also include a C-terminal extension consisting of one or more amino acids, including NP or NPVTPK (SEQ ID NO: 104).
The polypeptide can further include one or more fusion components attached to the polypeptide C-terminus via a linker, including Fc domain monomer or Fc domain, albumin-binding peptide, fibronectin domain, and human serum albumin. The partial content also describes Fc CH3-CH3 interface substitutions to reduce dimerization, including charged amino acid substitutions, and an optional removal of terminal lysine.
The described chimera sequences and fusion architectures are used for ActRII ligand sequestration and modulation of signaling including activin A, activin B, myostatin, GDF-11, BMP-9, and BMP-10. The patent addresses therapeutic polypeptides intended to modulate myostatin, activin, and ActRII-related signaling and related physiological endpoints across multiple conditions.
Claims Coverage
The independent claim set is directed to an extracellular ActRII chimera polypeptide defined by specific SEQ ID NO variants and optional N-terminal truncation while retaining defined residues, with dependent claim coverage refining sequence variants and adding C-terminal extensions and C-terminal fusion components linked by a linker. In total, the consolidated claim coverage presents six inventive features.
Extracellular ActRII chimera sequence variants with optional N-terminal truncation
A polypeptide comprising an extracellular activin receptor type II (ActRII) chimera having a sequence of any one of SEQ ID NO: 1 through SEQ ID NO: 21 with defined X1-X9 residue substitutions, optionally truncated from the N-terminus by deletion of 1-9 amino acids, and retaining the two amino acids before the first cysteine.
Defined chimera sequence range for the extracellular ActRII chimera
The polypeptide of the preceding claim, wherein the chimera sequence corresponds to one of SEQ ID NOs: 22-43.
C-terminal amino-acid extension for the ActRII chimera polypeptide
The polypeptide of the preceding claim, further including a C-terminal extension consisting of one or more amino acids.
C-terminal extension consisting of NP or NPVTPK
The polypeptide of the preceding claim, wherein the C-terminal extension consists of NP or NPVTPK (SEQ ID NO: 104).
C-terminal fusion components attached via a linker
The polypeptide of the preceding claim, further including one or more specified fusion components attached to the polypeptide’s C-terminus via a linker.
Restricted sequences for polypeptides with specified fusion components
The polypeptide of the preceding claim, wherein the polypeptide has a sequence corresponding to one of SEQ ID NOs: 107-110 or 184-263.
Overall, the claim coverage centers on extracellular ActRII chimera polypeptides defined by specified SEQ ID NO variant sets and optional N-terminal truncation while retaining residues before the first cysteine, with dependent features adding C-terminal extensions and optional C-terminal fusion components attached via a linker.
Stated Advantages
Improve pharmacokinetics and stability of ActRII chimera architectures.
Reduce dimerization by charged mutations at the Fc CH3-CH3 interface.
Extend half-life via albumin-binding peptides, fibronectin domains, or serum albumin fusions.
Documented Applications
Therapeutic use for muscle weakness and atrophy, and for increasing lean/muscle mass and muscle strength via modulation of myostatin/activin A/activin B/BMP9 signaling [procedural detail omitted for safety].
Therapeutic use for increasing bone mineral density and bone strength and reducing bone resorption and bone loss [procedural detail omitted for safety].
Therapeutic use for increasing red blood cell levels (hemoglobin/hematocrit/RBC count) and erythropoiesis [procedural detail omitted for safety].
Therapeutic use for increasing platelet levels and platelet production [procedural detail omitted for safety].
Therapeutic use for increasing neutrophils [procedural detail omitted for safety].
Therapeutic use for reducing or treating fibrosis, including myelofibrosis [procedural detail omitted for safety].
Therapeutic use for preventing, slowing, or treating pulmonary hypertension [procedural detail omitted for safety].
Therapeutic use for reducing body weight/fat and improving glycemic parameters in metabolic disease, including Type 1 diabetes and Type 2 diabetes [procedural detail omitted for safety].
Method claim lists directed to specific disorders including DMD, FSHD, ALS, anemia/myelodysplastic syndrome, thrombocytopenia, neutropenia, myelofibrosis, PAH/PH subtypes, and obesity/Type 1 diabetes/Type 2 diabetes [procedural detail omitted for safety].
Modulation/sequestration context for ActRII ligands including activin A, activin B, myostatin, GDF-11, and BMP-9/10 signaling.
In vivo disease-model application for renal fibrosis using the UUO model.
In vivo disease-model application for pulmonary arterial hypertension using a monocrotaline (MCT) model.
In vivo disease-model application for obesity using a high-fat diet model.
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