Acceleron Pharma Inc.
TGF-BETA SUPERFAMILY HETEROMULTIMERS AND USES THEREOF

Abstract:

The present invention discloses heterodimers comprising endoglin-Fc and ALKI-Fc, or hetero dimers comprising endoglin-Fc and ALK2-Fc. The Fe domains can include amino acid mutations that promote heterodimer formation. In certain aspects, the disclosure provides heteromeric polypeptide complexes comprising a co-receptor of the TGF-beta superfamily and an extracellular domain of a type I serine/threonine kinase receptor of the TGF beta superfamily, an extracellular domain of a type II serine/threonine kinase receptor of the TGF-beta superfamily, or an additional co-receptor of the TGF-beta superfamily. In some embodiments, the disclosure provides heteromultimers comprising a ligand-domain of one or more co-receptor selected from: endoglin, Cripto-1, Cryptic, Cryptic family protein IB, CRIMI, CRIM2, BAMBI, BMPER, RGM-A, RGMB, hemojuvelin, betaglycan, and MuSK. In some embodiments, the disclosure provides soluble heteromultimers comprising a ligand-domain of a co-receptor and a ligand-binding domain of a type II receptor selected from: ActRIIA, ActRIIB. TGFBRII, BMPRII, and MISRII. In some embodiments, the disclosure provides soluble heteromultimers comprising a ligand-domain of a co-receptor and a ligand-binding domain of a type I receptor selected from: ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, and ALK7. In certain aspects, such TGF-beta superfamily heteromultimers may be used to regulate (promote or inhibit) growth of tissues or cells including, for example, bone and hematopoietic lineages, including red blood cells.