Tgf-beta superfamily type i and type ii receptor heteromultimers and uses thereof

Abstract

In certain aspects, the disclosure provides soluble heteromeric polypeptide complexes comprising an extracellular domain of a type I serine/threonine kinase receptor of the TGF-beta family and an extracellular domain of a type II serine/threonine kinase receptor of the TGF-beta family. In some embodiments, the disclosure provides soluble 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 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 to regulate (promote or inhibit) growth of tissues or cells including, for example, muscle, bone, cartilage, fat, neural tissue, tumors, cancerous cells, and/or cells of hematopoietic lineages, including red blood cells. In certain aspects, such soluble polypeptide complexes are can be used to improve muscle formation, bone formation, hematopoiesis, metabolic parameters, and disorders associated with these tissues, cellular networks, and endocrine systems.

1 - 204 . (canceled) 
     
     
         205 . A recombinant heteromultimer comprising an ALK5 polypeptide and an ActRIIB polypeptide. 
     
     
         206 . The heteromultimer of  claim 205 , wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 29-109 of SEQ ID NO: 1. 
     
     
         207 . The heteromultimer of  claim 205 , wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 25-131 of SEQ ID NO: 1. 
     
     
         208 . The heteromultimer of  claim 205 , wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that:
 a) begins at any one of amino acids residues 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 SEQ ID NO: 1, and   b) ends at any one of amino acids residues 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134 of SEQ ID NO: 1.   
     
     
         209 . The heteromultimer of any one of  claim 205 , wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID Nos: 1, 2, 3, 4, 5, 6, 100, 102, 153, 154, 401, 402, 453, and 454. 
     
     
         210 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 36-106 of SEQ ID NOs: 30 or 87. 
     
     
         211 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 25-126 of SEQ ID NOs: 30 or 87. 
     
     
         212 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that:
 a) begins at any one of amino acids residues 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36 SEQ ID NO: 30 or 87, and   b) ends at any one of amino acids residues 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, and 126 of SEQ ID NO: 30 or 87.   
     
     
         213 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID Nos: 30, 31, 87, 88, 139, 141, 179, 180, 423, 424, 471, and 472. 
     
     
         214 - 495 . (canceled) 
     
     
         460 - 461 . (canceled) 
     
     
         498 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 90% identical to amino acids 36-106 of SEQ ID NOs: 30 or 87, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to amino acids 29-109 of SEQ ID NO: 1. 
     
     
         499 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 36-106 of SEQ ID NOs: 30 or 87, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 95% identical to amino acids 29-109 of SEQ ID NO: 1. 
     
     
         500 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises an amino acid sequence that is at least 99% identical to amino acids 36-106 of SEQ ID NOs: 30 or 87, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 99% identical to amino acids 29-109 of SEQ ID NO: 1. 
     
     
         501 . The heteromultimer of  claim 205 , wherein the ALK5 polypeptide comprises the amino acid sequence corresponding to amino acids 36-106 of SEQ ID NOs: 30 or 87, and wherein the ActRIIB polypeptide comprises the amino acid sequence corresponding to amino acids 29-109 of SEQ ID NO: 1. 
     
     
         502 . The heteromultimer of  claim 498 , wherein the heterologous domain of the ALK5 polypeptide and the heterologous domain of the ActRIIB polypeptide each comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain. 
     
     
         503 . The heteromultimer of  claim 499 , wherein the heterologous domain of the ALK5 polypeptide and the heterologous domain of the ActRIIB polypeptide each comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain. 
     
     
         504 . The heteromultimer of  claim 500 , wherein the heterologous domain of the ALK5 polypeptide and the heterologous domain of the ActRIIB polypeptide each comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain. 
     
     
         505 . The heteromultimer of  claim 501 , wherein the heterologous domain of the ALK5 polypeptide and the heterologous domain of the ActRIIB polypeptide each comprises an Fc immunoglobulin domain, wherein the Fc immunoglobulin domain is an IgG1 immunoglobulin domain. 
     
     
         506 . The heteromultimer of  claim 498 , wherein a linker domain is positioned between the ALK5 domain and the heterologous domain and/or a linker domain is positioned between the ActRIIB domain and the heterologous domain. 
     
     
         507 . The heteromultimer of  claim 499 , wherein a linker domain is positioned between the ALK5 domain and the heterologous domain and/or a linker domain is positioned between the ActRIIB domain and the heterologous domain. 
     
     
         508 . The heteromultimer of  claim 500 , wherein a linker domain is positioned between the ALK5 domain and the heterologous domain and/or a linker domain is positioned between the ActRIIB domain and the heterologous domain. 
     
     
         509 . The heteromultimer of  claim 501 , wherein a linker domain is positioned between the ALK5 domain and the heterologous domain and/or a linker domain is positioned between the ActRIIB domain and the heterologous domain. 
     
     
         510 . A method of treating a muscle disorder and/or neuromuscular disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the heteromultimer of  claim 205  to the subject.