Single-arm type I and type II receptor fusion proteins and uses thereof
In certain aspects, the disclosure provides soluble single-arm heteromeric polypeptide complexes comprising an extracellular domain of a type I serine/threonine kinase receptor of the TGF-beta family or an extracellular domain of a type II serine/threonine kinase receptor of the TGF-beta family. In some embodiments, the disclosure provides soluble single-arm polypeptide complexes comprising an extracellular domain of a type II receptor selected from: ActRIIA, ActRIIB, TGFBRII, BMPRII, and MISRII. In some embodiments, the disclosure provides soluble single-arm polypeptide complexes comprising an extracellular domain of a type I receptor selected from: ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, and ALK7. Optionally the soluble complex is a heterodimer. In certain aspects, such soluble polypeptide complexes may be used for the treatment or prevention of various TGF-beta associated conditions, including without limitation diseases and disorders associated with, for example, cancer, muscle, bone, fat, red blood cells, metabolism, fibrosis and other tissues that are affected by one or more ligands of the TGF-beta superfamily.
1. A recombinant protein complex comprising a first polypeptide covalently or non-covalently associated with a second polypeptide, wherein:
a. the first polypeptide comprises an ActRII polypeptide comprising an amino acid sequence that is at least 97% identical to SEQ ID NO: 404; and
b. the second polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 426;
wherein the protein complex is capable of binding to one or more of activin A, activin B, GDF8 and/or GDF11.
2. The recombinant protein complex of claim 1 , wherein the first polypeptide comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 404, and wherein the second polypeptide comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 426.
3. The protein recombinant complex of claim 1 , wherein the first polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 404, and wherein the second polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 426.
4. The recombinant protein complex of claim 1 , wherein the first polypeptide consists of amino acid sequence SEQ ID NO: 404, and wherein the second polypeptide consists of amino acid sequence SEQ ID NO: 426.
5. The recombinant protein complex of claim 1 , wherein the protein complex is a recombinant heterodimer.
6. The recombinant protein complex of claim 1 , wherein the protein complex exhibits weak or substantially no binding to BMP9 and/or BPM10.
7. The recombinant protein complex of claim 1 , wherein the protein complex inhibits the activity of one or more TGF-beta superfamily ligands in a cell-based assay, wherein the TGF-beta superfamily ligand is selected from: GDF8, GDF11, activin A and/or activin B.
8. The recombinant protein complex of claim 1 , wherein the first polypeptide and/or second polypeptide comprises one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety.
9. The recombinant protein complex of claim 1 , wherein the first polypeptide or the second polypeptide is glycosylated and has a glycosylation pattern obtainable from expression in a CHO cell.
10. The recombinant protein complex of claim 1 , wherein the protein complex has one or more of the following characteristics: i) binds to a TGF-beta superfamily ligand with a K D of less than or equal to 10 −7 ; and ii) inhibits a TGF-beta superfamily type I and/or type II receptor-mediated signaling transduction a cell.
11. A pharmaceutical preparation comprising the recombinant protein complex of claim 1 , and a pharmaceutically acceptable carrier.