ALK4:actriib heteromultimers and uses thereof
Inventors
Kumar, Ravindra • Grinberg, Asya • Sako, Dianne • Pearsall, Robert Scott • Castonguay, Roselyne
Assignees
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Publication Number
US-12258380-B2
Publication Date
2025-03-25
Expiration Date
Abstract
In certain aspects, the disclosure provides soluble heteromeric polypeptide complexes comprising an extracellular domain of an ALK4 receptor and an extracellular domain of ActRIIB. In certain aspects, such soluble ALK4:ActRIIB complexes may be used to regulate (promote or inhibit) growth of tissues or cells including, for example, muscle, bone, cartilage, fat, neural tissue, tumors, and/or cancerous cells. In certain aspects, such ALK4:ActRIIB complexes are can be used to improve muscle formation, bone formation, metabolic parameters, and disorders associated with these tissues, cellular networks, kidney, and endocrine systems.
Core Innovation
The invention relates to soluble recombinant ALK4:ActRIIB extracellular heteromultimers, preferably ALK4:ActRIIB heterodimers, that act as selective antagonists of TGF-beta superfamily ligands. The heteromultimers bind activin B and display altered binding selectivity compared with homodimers, including enhanced activin B binding while retaining activin A binding and retaining GDF8/GDF11 binding and/or substantially reduced binding to BMP9/BMP10/GDF3.
The document describes ALK4:ActRIIB antagonists with specific ALK4 polypeptide and ActRIIB polypeptide sequence identities and fusion protein architectures comprising heterologous domains. The antagonists are characterized by binding and inhibition profiles directed to activin B and related activin ligands, with reduced binding to non-target ligands such as BMP9, BMP10, and GDF3.
The document also describes therapeutic uses focused on kidney fibrosis and kidney inflammation using a recombinant ALK4:ActRIIB heteromultimer that binds activin B. It further includes screening assay concepts for identifying antagonists by modulating ALK4:ActRIIB heteromultimer ligand binding, including complex formation inhibition and/or potentiation.
Claims Coverage
The independent claim is directed to treating kidney fibrosis and/or kidney inflammation by administering a recombinant ALK4:ActRIIB heteromultimer that binds activin B, with defined sequence identity ranges for the ALK4 and ActRIIB polypeptides and optional fusion-protein architecture. Dependent claims refine the treated condition and tighten structural and sequence-identity requirements, including a specific heterodimer form.
Recombinant ALK4:ActRIIB heteromultimer for activin B binding
A method for treating kidney fibrosis and/or kidney inflammation by administering a recombinant ALK4:ActRIIB heteromultimer comprising an ALK4 polypeptide and an ActRIIB polypeptide, where the heteromultimer binds to activin B.
High sequence identity ALK4 and ActRIIB polypeptides
The ALK4 polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 34-101 of SEQ ID NO: 9, and the ActRIIB polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 29-109 of SEQ ID NO: 1.
Fusion protein with heterologous domain
The ALK4 polypeptide and/or the ActRIIB polypeptide is a fusion protein further comprising a heterologous domain.
ALK4:ActRIIB heterodimer form
The heteromultimer is an ALK4:ActRIIB heterodimer.
Linker domain positioning in fusion protein
A fusion protein contains one or more linker domains positioned between the ALK4 domain and the heterologous domain and/or between the ActRIIB domain and the heterologous domain.
Overall, the claim set centers on administering a recombinant ALK4:ActRIIB heteromultimer, including an ALK4:ActRIIB heterodimer, that binds activin B, using ALK4 and ActRIIB polypeptides with specified high sequence identity to defined SEQ ID regions and optionally incorporating fusion proteins with heterologous domains and linker domain positioning.
Stated Advantages
Selective ligand antagonism with altered binding selectivity versus homodimers, including enhanced activin B binding while retaining activin A/GDF8/GDF11 binding and substantially reduced BMP9/BMP10/GDF3 binding.
Anabolic effects on skeletal muscle and bone.
Catabolic effects on adipose.
Potential to avoid angiogenesis effects via reduced BMP9/10 antagonism.
Delaying or preventing progression of kidney disease stages across chronic kidney disease stages (stage 1 to stage 2, stage 2 to stage 3, stage 3 to stage 4, or stage 4 to stage 5).
Documented Applications
Treating kidney fibrosis and/or kidney inflammation in a patient in need thereof by administering a recombinant ALK4:ActRIIB heteromultimer that binds activin B.
Delaying or preventing progression of kidney disease across chronic kidney disease stages (stage 1-5).
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