Soluble bone morphogenetic protein (BMP) receptor type-1b proteins and uses for the treatment of vascular inflammation

Abstract

This application relates generally to the field of Bone Morphogenetic Protein (BMP) antagonists (soluble ALK6 fusion proteins), compositions thereof, and methods for use in treating vascular inflammation diseases.

Description

1902004-0002-004-W01SOLUBLE BONE MORPHOGENETIC PROTEIN (BMP) RECEPTOR TYPE-1B PROTEINS AND USES FOR THE TREATMENT OF VASCULAR INFLAMMATION

[0001] RELATED APPLICATIONS

[0002] This application claims priority to United States provisional application Ser. No.63 / 753,319 filed on 03 February 2025 and United States provisional application Ser. No.63 / 757,624 filed on 12 February' 2025, each of which is incorporated by reference into this application in its entirely.

[0003] SEQUENCE LISTING

[0004] The instant application contains a sequence listing which has been submitted electronically in ASCII format via the USPTO Patent Center and hereby incorporated by reference in its entirety. Said ASCII copy, created on 30 January’ 2026, is named 1902004-0002-004-W01 __SL.xml and is 655,562 bytes in size.

[0005] FIELD OF THE DISCLOSURE

[0006] This application relates generally to the field of Bone Morphogenetic Protein (BMP) antagonists, compositions thereof, and methods for use in treating diseases related to BMPs.

[0007] BACKGROUND OF THE DISCLOSURE

[0008] Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation.

[0009] Calcification of the arterial intima is another prominent feature of atherosclerotic plaque development and seems to be critically regulated by bone morphogenic proteins (BMPs), similar to actual bone formation during organism development. BMPs are phylogenetically conserved signaling molecules of the transforming growth factor¬ superfamily. Their function in embryogenesis has been extensively studied, but their biological role after birth remains to be fully elucidated. Recent evidence has implicated BMP-2 and -4 in vascular inflammation. BMP -4 plays a critical role in early atherogenesis in vascular regions subjected to d4isturbed blood flow and activates arterial NADPH oxidases1902004-0002-004-W01leading to endothelial dysfunction and hypertension. Noggin, a BMP antagonist, prevents these effects and may therefore be a novel remedy to early atherosclerosis formation. Recent evidence further suggests that BMP -2 and -4 may have distinct roles in vascular atherogenesis in hyperglycemia with BMP-4 inducing more proangiogenic effects and BMP-2 more pro-calcific effects. BMP antagonists are secreted proteins with a cysteine-knot structure that prevents interaction of BMPs with their receptors. Interestingly, noggin is coexpressed with BMP-4 in endothelial cells exposed to proatherogenic flow conditions and plays a negative feedback role against the inflammatory response of BMP -4. Although BMP- 4 is preferentially expressed by endothelial cells, BMP-2 is expressed in both the endothelium and the media. Noggin is also expressed throughout the vessel wall, suggesting it may be particularly important for inhibiting BMP -2 based on similar distribution.

[0010] Increased BMP-2 and BMP -4 expression at atherosclerotic sites potentiates such calcification, whereas pharmacological inhibitors of BMP signaling or the BMP antagonist MGP can reduce vascular inflammation and calcification. Indeed, MGP overexpression attenuates vascular calcification in− / −mice.

[0011] BMPs play roles in macrophage differentiation and modulate the inflammatory response. BMP -2 and BMP -4, which can be produced by atherosclerotic VSMCs, promote BMPRII-dependent monocyte attraction leading to inflammation of the atherosclerotic lesion. BMP-6 can activate Ml macrophages, and stimulates IL-6 expression dependent on ALK-2, Smadl, and p38 MAPK.

[0012] It has been reported that BMP-2, -4, -6 and -7 induce angiogenesis, EC proliferation and migration. Capillary tube formation is increased upon activation of the BMP signaling pathway by overexpression of BMPs.

[0013] The transforming growth factor-beta (TGF-beta) superfamily contains a variety of growth factors that share common sequence elements and structural motifs. These proteins are known to exert biological effects on a large variety of cell types in both vertebrates and invertebrates. Members of the superfamily perform important functions during embry onic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, osteogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. The family is divided into two general phylogenetic clades: the more recently evolved members of the superfamily, which includes TGF-betas, Activins, and nodal and the clade of more distantly- related proteins of the superfamily, which includes a number of BMPs and GDFs. Hinck (2012) FEBS Letters 586:1860-1870. TGF-beta family members have diverse, often complementary1902004-0002-004-W01biological effects. By manipulating the activity of a member of the TGF-beta family, it is often possible to cause significant physiological changes in an organism. For example, the Piedmontese and Belgian Blue cattle breeds carry' a loss-of-function mutation in the GDF8 (also called myostatin) gene that causes a marked increase in muscle mass. Grobet et al. (1997) Nat Genet., 17( 1):71-4. Furthermore, in humans, inactive alleles of GDF8 are associated with increased muscle mass and, reportedly, exceptional strength. Schuelke et al. (2004) N Engl J Med, 350:2682-8. Changes in muscle, bone, fat, red blood cells, and other tissues may be achieved by enhancing or inhibiting signaling (e.g., SMAD 1, 2, 3, 5, and / or 8) that is mediated by ligands of the TGF-beta family.|0014] Unbalanced BMP signaling is involved in several human vascular diseases, caused directly by mutations in BMP signaling components or indirectly by alteration of signaling levels. Together with evidence from numerous genetic animal models, these genetic correlations provide clear support for the view that BMP signaling plays a crucial role in vascular remodeling. BMPs exert potent effects on the capacity of endothelial cells to migrate, proliferate, and form basic tubular structures. BMPs also help determine the fates of the surrounding pericytes, VSMCs, and adventitial cells that contribute to vessel structural integrity and function. BMP inhibition may be useful in the treatment of vascular disorders, such as CCM, vascular calcification and atherosclerosis.

[0015] Thus, there is a need for agents that regulate the activity’ of various ligands of the TGF-beta superfamily, including the bone morphogenetic proteins (BMPs) related to this disclosure.

[0016] SUMMARY OF THE DISCLOSURE

[0017] Described herein are polypeptides, compositions, other reagents related to Bone Morphogenetic Protein (BMP) antagonists, and methods for use in treating vascular inflammation disorders related to BMP ligand and endogenous signaling. In particular, this disclosure relates to soluble bone morphogenetic protein (BMP) receptor type IB polypeptides comprising an extracellular domain of ALK6 (activin receptor-like kinase 6) and soluble vanants thereof (“ALK6 polypeptides”), which bind BMP ligands and sequester the ligands from binding to their receptors (“BMP antagonists”). The ALK-6 polypeptides of this disclosure bind BMP ligands, including, but not limited to BMP 4, 6, 7 and / or 10. in certain embodiments, ALK-6 polypeptides of this disclosure bind BMP 10. In certain embodiments, the ALK6 ECD sequence may comprise one or more point mutations, addition or deletion of c-terminal residues, wherein position 60 is glycine (G) as provided in SEQ ID NO:1.1902004-0002-004-W01

[0018] In embodiments, proved herein are methods for treatment of vascular inflammation in a human subject in need thereof comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence selected from SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 108; SEQ ID NO: 109; SEQ ID NO: 130, SEQ ID NO: 157, SEQ ID NO: 190 and SEQ ID NO: 437.

[0019] In certain embodiments provided herein are methods for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising an ALK6 ECD polypeptide, a linker and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158-189, 191- 194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277283, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431

[0020] In certain embodiments provided herein are methods for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 ECD polypeptide, a linker and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 86, SEQ ID NO: 88 or SEQ ID NO: 90.1902004-0002-004-W01

[0021] In embodiments, the vascular inflammation disorder is selected from atherosclerosis, kidney failure, liver steatosis, obesity, diabetes, restenosis, lung fibrosis, pulmonary arterial hypertension (PAH) right sided heart failure and pulmonary hypertension (PH) righ t sided heart failure. In certain embodiments the vascular inflammation disorders are selected from pulmonary hypertension (PH), pulmonary arterial hypertension right sided heart failure, pulmonary arterial hypertension (PAH), cardiovascular disease, cardiac calcification, atrial fibrillation, diabetic or primary cardiomyopathy (DCM), myocardial hypertrophy, cardiac hypertrophy, myocardial fibrosis, vasculitis, Giant cell arteritis, Granulomatosis with polyangiitis (GPA), Buerger's disease, IgA vasculitis, Kawasaki disease, Takayasu arteritis, Fibromuscular dysplasia (FMD), Primary lymphedema, Secondary lymphedema, diabetic ulcers, and diabetic nephropathy. In certain embodiments, the vascular inflammation disorder is a peripheral artery disease, wherein optionally the peripheral artery disease is selected from Intestinal ischemic syndrome, Renal artery disease, Popliteal Entrapment Syndrome, Raynaud's Phenomenon, Buerger's Disease and lymphedema. In embodiments, the vascular inflammation disorder is diabetic cardiomyopathy (DCM) or diabetic nephropathy.

[0022] In embodiments provided herein are methods for the treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID NO: 91, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432. In embodiments, the fusion protein 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 SEQ ID NO: 287

[0023] In certain embodiments, provided herein are methods for the treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, yvherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, yvherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,1902004-0002-004-W0199%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431. In certain embodiments, the ALK6 ECD 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 SEQ ID NO: 286.

[0024] In embodiments, treating comprises reducing microvascular endothelial dysfunction, reducing metabolic inflammation, reducing hyperglycemia and / or reducing immune inflammation.

[0025] In embodiments, the ALK6 ECD 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 SEQ ID NO: 69; SEQ ID NO: 90; and SEQ ID NO: 286. In other embodiments, the ALK6 ECD 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 SEQ ID NO: 190. In certain embodiments, the ALK6 ECD 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 SEQ ID NO: 90. In certain embodiments, the ALK6 ECD 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 SEQ ID NO: 286.

[0026] In embodiments provided herein are soluble recombinant bone morphogenetic protein receptor type- IB fusion proteins comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence selected from SEQ ID NO: 130; SEQ ID NO: 157, SEQ ID NO: 190; and SEQ ID NO: 437. In certain embodiments, the ALK6 ECD 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 an ALK6 ECD sequence selected from 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431.1902004-0002-004-W01

[0027] In other embodiments provided herein are soluble recombinant bone morphogenetic protein receptor type-lB fusion proteins comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 130: Lysi - Lys?, - Glus - Asp 4 - Glys - Glus - Ser? - Thrs - Alas - Proio - Thru - Proi? - Argis -Prou - Lysis - Xaais - Leun - Argis - Cysis - Xaaso -Cys2i—Xa 22- Xaa 22- Xaa 22~ aa23—Xaa 23 - Xaa??—Cys25—Pro26 - Xaa.27—Asp?? - Xaa?? - Xaaso - Asnsi - Asns2 - Xaass - Cyssi - Xaass - Thrss - Xaas? - Glyss - Xaass - Cysio - Phen - Xaai?. - Xaais - Ile44 Glu45 Glu46 - Aspi? - Aspis - Xaais - Glyso - Xaasi - Xaas?. - Xaass -Xaa- 1 - Xaass - Serss - Glys? - Cysss - Xaass - Xaaso - Xaasi - Ghi62 - Glyss - Sers4 - Aspss -Phe66 - Gln67 – Cys68 - Xaass - Aspro - Xaa?i - Pro?? - Xaa?3 - Xaasi - Xaa?s - Xaa?s - Arg?? -Arg?s - Xaa?9 - Ileso - GIusi - Cyss?. - Cysss - Xaasi - Xaass - Xaass - Xaas? - Xaass - Cysss - Asnso - Xaasi - Xaas? - Leuss - Xaasi - Pross - Thrss - Leus? - Press - Pross - Leuioo - Lysioi - Asn102 - Argios - Aspioi - Pheios - Valios - Xaaio? - Xaaios - Xaaios - Xaauo - Xaam - Xaan? - Xaai is; wherein Xaa16 is V or I; Xaa?o is V, F, K, Y, T, or A; Xaa22 is G, E, H or S; Xaa’22 is absent, G, S, or A; Xaa’ 22 is absent or S; Xaass is S, H, G, or L; Xaa’23 is absent or L; Xaa?.i is H or S; Xaa27 is E or D; Xaa.29 is S or A; Xaaso is V or I; Xaa33 is I or T; Xaa35 is S or I; Xaas? is D or N; Xaa38 is F or H; Xaai2 is T or A; Xaais is M or I; Xaais is S or Q; Xaasi is M, L or E; Xaa.52 is P or T; Xaa.53 is V or T; Xaa54 is V or L; Xaa55 is T or A; Xaa59is L or M; Xaa60is G or K; Xaa61 is L or Y; Xaa69is R or K; Xaa71 is T or S; Xaa73 is I or K; Xaa74is P or A; Xaa?s is FI or Q; Xaa76is Q or L; Xaa?s is S or T; Xaa84 is T or R; Xaa85 is absent, T or E; Xaa86is R or N; Xaas? is N or L; Xaa88 is absent, E or L; Xaa91 is K or Q; Xaa92is D or L; Xaa94 is H or Q; Xaaio? is absent; Xaaios is absent; Xaaios is absent; Xaauo is absent; Xaai 11 is absent; Xaam. is absent; and, Xaam is absent.

[0028] In some embodiments, Xaa60 is a glycine (G) residue. In some embodiments, the polypeptide binds BMP10. In some embodiments, the fusion protein further comprises a linker sequence. In some embodiments, the fusion protein further comprises a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the Fc comprises an amino acid sequence according to SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the Fc sequence is according to SEQ ID NO: 106.

[0029] In other embodiments provided herein are soluble recombinant bone morphogenetic protein receptor type- IB fusion proteins comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 157 Xaai - Xaa? - Xaas - Xaai - Xaas - Xaas - Xaa? - Xaas1902004-0002-004-W01-- Xaa? - Xaaio - Xaau Xaai 2 - Xaai3 - Xaai4 - Xaais - Xaau - Leun --- Argis - Cysi9 - Xaa?o - Cys2i - Xa 22 - Xaa’ 22 - Xa ”22 - Xaa23 - Xaa’23 - Xa 24 - Cys25 - Pro?6 - Xaa27 - Asp28 - Xaa29 - Xaaso - Asiui - Asr - Xa 33 - Cys34 - Xaau - Thru - Xaa?7 - Gl '38 - Xaa39 - Cys4o - Phe i - Xaa42 - Xa 3 - Ile44 - GI1145 - G1U46 - Asp47 - Asp48 - Xaa49 Glyso - Xaasi - Xaa.52 - Xaas 3 - Xaa54 - Xaass - Scrss - Glys? - Cysss - Xaass - Xaaeo - Xaaei - Glu62 - Gly63 - Sers4 -Aspss - Phese - Gin? - Cysss - Xaao9 - Asp?o - Xaa?i - Pro72 - Xaa73 - Xa?4 - Xaa.75 - Xaa?6 -Arg77 - Arg78 - Xaa?9 - Ileso - Glusi - Cyss? - Cyss? - Xaas - Xaau - Xaau. - Xaas? - Xaass -Cys89 - Asnoo - Xaaoi - Xaa9?_ - Leu93 - Xa 94- Progs - Throe- Leu97 - Proos - Pro99 - Xaaioo -Xaaioi - Xaaio2 - Xaaioo - Xaaio4 - Xaaios - Xa io6 - Xaaio? - Xaaios - Xaaio - Xaano - Xaam - Xaa - Xaam wherein: Xaai is K or absent; Xaa? is K or absent; Xaa? is E or absent; Xaa4 is D or absent; Xaas is G or absent, Xaae is E or absent; Xaa? is S or absent; Xaas is T or absent; Xaa9 is A or absent; Xaaio is P or absent; Xaau is T or absent; Xaa is P or absent; Xaau is R or absent; Xaau is P or absent, Xaau is K, P or absent; Xaau is V or absence; Xaa20 is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y; Xaa22 is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S; Xaa’ 22 is absent, G, S, or A; X aa'? is absent or S; Xaa23 is S, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G; Xaa’23 is absent, L or H; Xaa24 is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y; Xaa27 is E or D; Xaa?9 is S, G or A; Xaaao is V, A, G or I; Xaa?3 is I, S or T; Xa 35 is S, T, G, A or I; Xaa37 is D, A, G or N; Xaa39 is Y, A, G or H; Xa 42 is T or A; Xaa 3 is M or I; Xaa49 is S, A, G or Q; Xaa51is L, A, G or E; Xaa52 is P or T; Xaass is V, A, G or T; Xaa54 is V, A, G or L; Xaa₅₅ is T, G or A; Xaa59 is L, M, V, F, K, A, R, N, D, C, E, Q, G, H, I, P, S, T, W, or Y; Xaa60 is G, K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T, W, or Y; Xaa61 is L, Y, V, F, K, A, R, N, D, C, E, Q, G, H, I, M, P, S, T, or W; Xaa69 is R or K; Xaan is T or S; Xaa73 is I or K; Xaa74is P or A; Xaa?s is H or Q; Xaa76is Q or L; Xaa79is S or T; Xaa84 is T, R or absent; Xaa85 is absent, T or E; Xaa86 is R, N or absent; Xaa87 is N, L or absent; Xaa88 is absent, E or L; Xaa91 is K, Q or absent; Xaa92 is D, L, Y or absent; Xaa94 is H, Q or absent; Xaa100 is absent, V or L; Xaa101 is absent, V or K; Xaa102 is absent, I or N; Xaa103 is absent, G or R; Xaa104 is absent, P, D or A; Xaa105 is absent or F; Xaai os is absent, F, W, Y, N, Q, K, II, D, G, E or V; Xaa107 is absent, L, M, V, F, K, A, R, N, C, E, Q, G, H, I, P, S, T, W, or Y or D; Xaa108 is absent, R, T, Q, L, K, W or G; Xaa109 is absent, S or P; Xaa110 is absent or I; Xaa111 is absent, R or H; Xaa112 is absent or H; and Xaa113 is absent or R,

[0030] In certain embodiments, the ALK6 ECD sequence comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,1902004-0002-004-W0196%, 97%, 98%, 99%, or 100% identical to a sequence selected from any one of SEQ ID NO: 132 to 155.|0031 ] In some embodiments, the fusion protein further comprises a linker sequence. In some embodiments, the fusion protein comprises a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the Fc 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 the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107, In some embodiments, the Fc comprises the amino acid sequence of SEQ ID NO: 106.10032] In certain embodiments, the Xaa60 is a glycine (G) residue and the fusion protein binds BMP 10.

[0033] In some embodiments, the ALK6 ECD sequence 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 sequence selected from any one of SEQ ID NO: 132 to 155.

[0034] In other embodiments provided herein are soluble recombinant bone morphogenetic protein receptor type- IB fusion proteins comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 190 Lysi - Lys?. - Glus - Aspr - Glys - Glus - Ser? - Thrs - Alas - Proio - Thru - Proi2 - Argu -Proi4 - Xaais - Xaais - Leui? - Argis - Cysis - Xaaso - Cys2i - Xaa22 - Xaa’22 - Xaa’22 - Xaa23 - Xaa’23 - Xaa24 - Cys25 - Pro26 - Xaa? - Asp28 - Xaa29 - Xaaso - Asn31 – Asn32 - Xaass - Cys34 – Xaa35 - Thns - Xaas? - Glyss - Xaa39 - Cys o - Phe i - Xaa42 – Xaa43 – Ile44 - Glu45 - Glu46 - Asp47 - Aspis - Xaa49 - Glyso - Xaasi - Xaa52 – Xaa53 -Xaa54 – Xaa55 - Serss - Glys? - Cysss - Xaass - Xaaso - Xaasi - Glu62 – Gly63 - Sers4 - Aspss - Phess - Gln67 – Cys68 - Xaa69 – Asp70 - Xaa?i - Pro?2 - Xaa?3 - Xaa?4 - Xaa?s - Xaa?6- Arg77 – Arg78 - Xaa?9 - Ileso - Glusi - Cys82 – Cys83 - Xaas4 - Xaass - Xaass - Xaas? - Xaass - Cyss9 - Asngo - Xaa9i - Xaa92 - Leu93 - Xaa94 – Pro95 – Thr96 - Leu97 - Press - Pro99 - Leuioo - Lysioi -Asnio? - Argios - Xaaio4 - Pheios - Valios - Xaaio? - Xaaios - Xaaio9 - Xaano - Xaam - Xaam - Xaam; wherein Xaa15is K or P; Xaa16 is V or I; Xaa?o is V, F, K, A, R, N, D, C, E, Q, G, II, I, L, M, P, S, T, W, or Y; Xaa22 is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S; Xaa’22 is absent, G, S, or A; Xaa”22 is absent or S: Xaa?3 is S, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G; Xaa’23 is absent, L or H; Xaa24 is V, F, K, A, R, N, D, (. E, Q, G, H, I, L, M, P, S, T, W, or Y; X a2? is E or D; Xa 29 is S, G or A; Xaa30is V, A, G or I; Xaass is I,1902004-0002-004-W01S or T; Xaass is S. T, G, A or I; Xaa37is D, A, G or N; Xaa39 is Y, A, G or H; Xaa42is T or A; Xaa43 is M or 1; Xaa49 is S, A, G or Q; Xaa51is L, A, G or E; Xaa52 is P or T; Xaass is V, A, G or T; Xaas4 is V, A, G or L; Xaa₅₅ is T, G or A; Xaas9 is L, M, V, F, K, A, R, N, D, C, E, Q, G, H, I, P, S, T, W, or Y; Xaaeo is G, K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T, W, or Y; Xaaei is L, Y, V, F, K, A, R, X, D, C, E, Q, G, H, I, M, P, S, T, or W; Xaas, is R or K; Xaa71 is T or S; Xaa73 is I or K; Xaa74 is P or A; Xaa75 is H or Q; Xaa76 is Q or L; Xaa79is S or T; Xaa«4 is T, R or absent; Xaa85 is absent, T or E; Xaa86 is absent, R or N; Xaa87 is N or L; Xaa88 is absent, E or L; Xaa91 is absent, K or Q; Xaa92 is absent, D, Y or L; Xaa94 is absent, H or Q; Xaaio4 is D or A; Xaaio? is absent; Xaaiog is absent; Xaaio9 is absent; Xaano is absent; Xaain is absent; Xaa112 is absent; and, Xaa113 is absent. In some embodiments, the polypeptide binds BMP 10.

[0035] In some embodiments, the fusion protein further comprises a linker sequence. In some embodiments, the fusion protein comprises a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the Fc 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 the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the Fc comprises the amino acid sequence of SEQ ID NO: 106.

[0036] In some embodiments, the ALK6 ECD sequence 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 sequence selected from any one of SEQ ID NO: 132 to 155.

[0037] In certain embodiments, the ALKA ECD sequence 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 sequence selected from any one of SEQ ID NO: 158 to 189.

[0038] In other embodiments provided herein are soluble recombinant bone morphogenetic protein receptor type-lB fusion proteins comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 437 Lysi - Lys?. - Glus - Aspr - Glys - Glus - Ser? - Thrg -Alas - Proio - Thr11 – Pro12 – Arg13 -Proi 4 - Xaais - Xaais - Leui? - Argis - Cys19 – Xaa20 -Cys2i - Xaa22 - Xaass - His24 - Cysss - Pro26 - Xaa2? - Aspss - Xaa29 – Xaa30 – Asn31 – Asn32 -Xaass - Cys34 - Xaass - Thrss - Xaa37 - Glysg - Xaass - Cys40 – Phe41 – Xaa42 – Xaa43 – Ile44 -1902004-0002-004-W01G1U45 - G1U46 - Asp47 - Asprs - Xaa49 - Glyso - Xaasi - Xaas2 - Xaasa, - Xaas 4 - Xaass - Serss - Gly57 - Cys58 - Xaass - Xaaso - Xaasi - Glu62 - Glys.i - Ser64 - Aspss - Phees - Glue? - Cyses - Xaa«9 - Asp?o - Xaa?i - Pro?2 - Xaa?3 - Xaa-: - Xaa?s - Xaa?6 - Arg77 - Arg78 - Xaa?9 - Ileso - Glu8i - Cys82 - Cys 3 - Xaas4 - Xaass - Xaass - Xaas7 - Xaass - Xaas9 - Xaa9o - Xaa9i - Xaa92 - Xa 93 - Xaa94 — Xaa9s — a96 — a97 — Xaa s — Xa 99 - Xaaioo - Xaaioi_Xaaio2 * Xaaio3 - Xaaio4 ~ Xaaios - Xaaioo - Xaaior ~ Xaaios ■ X aio9 - Xaano - Xaam - Xaam - Xaaii3 wherein: Xaa15 is K or P; Xaa16 is V or I; Xaa20 is V, F, K or Y; Xaa22 is G, H or S; Xaa23 is S, H or G; Xaa27 is E or D; Xaa29 is S or A; Xaa30 is V or I; Xaa33 is I or T; Xaa35 is S or I; Xaa37 is D or N; Xaa39 is Y or H; Xaa42is T or A; Xaa43 is M or I; Xaa49 is S or Q; Xaa51 is L or E; Xaa52 is P or T; Xaa53 is V or T; Xaa54 is V or L; Xaa55 is T or A; Xaa59 is L or M Xaa60 is G or K; Xaa61 is L or Y; Xaa69 is R or K; Xaa71 is T or S; Xaa73 is I or K; Xaa74 is P or A; Xaa75 is H or Q; Xaa76 is Q or L; Xaa79is S or T; Xaa84 is T or R; Xaa85 is absent, T or E; Xaa86 is R or N; Xaa87 is absent, N or L; Xaa88 is absent, E or L; Xaa89 is absent or C; Xaa90 is absent or N; Xaa91 is absent, K or Q; Xaa92 is absent, D or L; Xaa93 is absent or L; Xaa94 is absent, H or Q; Xaa95 is absent or P; Xaa96 is absent or T; Xaa97 is absent or L; Xaa98 is absent or P; Xaa99 is absent or P; Xaa100 is absent, V or L; Xaa101 is absent, V or K; Xaa102 is absent, I or N; Xaa103 is absent, G or R; Xaa104 is absent, P, D or A; Xaa105 is absent or F; Xaa106 is absent, F or V; Xaa107 is absent or D; Xaa108 is absent or G; Xaa109 is absent, S or P; Xaa110 is absent or I; Xaa111 is absent, R or H; Xaa112 is absent or H; and Xaa113 is absent or R.

[0039] In some embodiments, Xaa60 is a glycine (G) residue. In some embodiments, the polypeptide binds one or more of BMP6, BMP 7 and / or BMP 10. In some embodiments, the fusion protein further comprises a linker sequence. In some embodiments, the fusion protein further comprises a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the heterologous sequence is an Fc sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the Fc sequence comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, the Fc sequence 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 the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the Fc comprises the amino acid sequence of SEQ ID NO: 106.

[0040] In embodiments, the ALK6 ECD sequence 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 sequence selected from any one of SEQ ID NO: 90,1902004-0002-004-W01286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, 431 and 440.|0041] In certain embodiments provided herein the soluble recombinant bone morphogenetic protein receptor type-lB fusion protein of this disclosure comprises an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence according to SEQ ID NO: 286.|0042] In other embodiments provided herein are the soluble recombinant bone morphogenetic protein receptor type- IB fusion protein of this disclosure comprise an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence (e.g. Fc sequence) wherein the fusion protein sequence 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 SEQ ID NO: 203-212, 214-217, 219-222, 224-227, 229-232, 234-241, 243-246, 248- 251, 253-256, 258-261, 263-266, 268-271, 273-276, 278-282, 284, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432.

[0043] In specific embodiments, the soluble recombinant bone morphogenetic protein receptor type-lB fusion protein of this disclosure comprises an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fission protein sequence 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 SEQ ID NO: 287.

[0044] Provided herein are soluble recombinant bone morphogenetic protein receptor type-lB fusion proteins comprising: an ALK6 extracellular domain (ECD), a linker sequence and an Fc domain sequence wherein tire ALK6 ECD sequence 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 an ALK6 ECD sequence selected from SEQ ID NO: 86 or 90, wherein amino acid position 60 is a glycine (G) residue. In embodiments, the ALK6 ECD sequence comprises at least one point mutation as compared to SEQ ID NO: 1, In embodiments, the point mutation is selected from K20Y, K20F, K20V, H22S, II22G, II23S, and H23G. In embodiments, the polypeptide binds BMP10.

[0045] In embodiments, the ALK6 ECD polypeptide is present as a homodimer.1902004-0002-004-W01

[0046] Provided herein are pharmaceutical composition comprising an ALK6 fusion protein of this disclosure; and, at least one pharmaceutical acceptable carrier or buffer. In embodiments, the ALK6 ECD polypeptide is present as a homodimer.

[0047] In certain embodiments provided herein are methods for treating vascular inflammation disorders including PAH, comprising administering an effective amount of a pharmaceutical composition comprising an ALK6 Fc fusion protein of this disclosure to a subject in need thereof.

[0048] Provided herein are methods for treatment of vascular inflammation in a human subject in need thereof comprising: administering an effective amount of a pharmaceutical composition to the subject.

[0049] In embodiments, provided herein is a method for treatment of vascular inflammation in a human subject in need thereof comprising: administering an effective amount of a pharmaceutical composition to the subject, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 ECD polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 108; SEQ ID NO: 109; SEQ ID NO: 130, SEQ ID NO: 157, SEQ ID NO: 190 and SEQ ID NO: 437.

[0050] In embodiments, provided herein is a method for treatment of vascular inflammation in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431.1902004-0002-004-W01

[0051] In certain embodiments, the ALK6 ECD sequence comprises at least one point mutation as compared to SEQ ID NO: 1. In certain embodiments, the soluble recombinant bone morphogenetic protein receptor type-lB fusion protein 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 SEQ ID NO: 86, SEQ ID NO: 88 or SEQ ID NO: 90.

[0052] In embodiments, provided herein is a method for treatment of vascular inflammation in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 3, 5, 79, 81, 82, 83, 108, 109, 112, 130, 157 or 190.

[0053] In certain embodiments, the ALK6 ECD 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 SEQ ID NO: 69. In some embodiments, the ALK6 ECD 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 SEQ ID NO: 90. In some embodiments, the ALK6 ECD 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 SEQ ID NO: 286. In some embodiments, the ALK6 ECD 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 SEQ ID NO: 233 or SEQ ID NO:242, In some embodiments, the ALK6 ECD sequence comprises at least one point mutation as compared to SEQ ID NO: 1. In some embodiments, the point mutation is selected from one or more of V16I; K20Y, K20F, H22S,. 22’ A, H23G, V301, I33T, I33S, S35I, S49Q and L51M In some embodiments, the heterologous sequence is an Fc sequence is an amino acid sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the heterologous sequence is an Fc sequence comprising the amino acid sequence of SEQ ID NO: 106. In some embodiments, the fusion protein binds one or more of BMP2, BMP4, BMP6, BMP7, GDF5, GDF6, GDF7 and / or BMP10. In some embodiments.1902004-0002-004-W01the polypeptide binds BMP10. In some embodiments, the polypeptide does not bind BMP10. In some embodiments, the ALK6 ECD sequence is selected from SEQ ID NO: 190 and the sequence comprises point mutations K20Y and H22S. In some embodiments, the ALK6 ECD sequence is selected from SEQ ID NO: 190 and the sequence comprises point mutations K20Y, H22S and 1331'. In some embodiments, the ALK6 ECD sequence is selected from SEQ ID NO: 190 and the sequence comprises point mutations H22S and I33T. In some embodiments, the heterologous region is an Fc region.

[0054] In some embodiments, the vascular inflammation disorder is selected from atherosclerosis, kidney failure, liver steatosis, obesity, diabetes, restenosis, lung fibrosis, pulmonary arterial hypertension (PAH) right sided heart failure and pulmonary hypertension (PH) right sided heart failure. In some embodiments, the vascular inflammation disorder is selected from pulmonary hypertension (PH), pulmonary arterial hypertension right sided heart failure, pulmonary' arterial hypertension (PAH), cardiovascular disease, cardiac calcification, atrial fibrillation, diabetic or primary'- cardiomyopathy (DCM), myocardial hypertrophy, cardiac hypertrophy, myocardial fibrosis, vasculitis, Giant cell arteritis, Granulomatosis with polyangiitis (GPA), Buerger's disease, IgA vasculitis, Kawasaki disease, Takayasu arteritis, Fibromuscular dysplasia (FMD), Primary' lymphedema, Secondary lymphedema, diabetic ulcers, and diabetic nephropathy. In some embodiments, the vascular inflammation disorder is a peripheral artery disease. In some embodiments, the peripheral artery disease is selected from Intestinal ischemic syndrome, Renal artery disease, Popliteal Entrapment Syndrome, Raynaud's Phenomenon, Buerger's Disease and lymphedema. In some embodiments, the vascular inflammation disorder is diabetic cardiomyopathy (DCM) or diabetic nephropathy.

[0055] In some embodiments of the methods for treating provided herein, treating comprises reducing microvascular endothelial dysfunction, reducing metabolic inflammation, reducing hyperglycemia and / or reducing immune inflammation. In some embodiments, the ALK-6 Fc fusion polypeptide is administered as monotherapy for the vascular inflammation disorder. In some embodiments, the ALK-6 Fc fusion polypeptide is administered as adjunct therapy with an additional treatment for the vascular inflammation disorder.

[0056] In embodiments, tire disclosure provides methods for treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof. In certain embodiments, the disclosure provides a method for treatment of pulmonary' arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an amino1902004-0002-004-W01acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID NO: 91, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432

[0057] In certain embodiments, the fusion protein 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 SEQ ID NO: 91. In certain embodiments, the fusion protein 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 SEQ ID NO: 287.

[0058] In embodiments, the disclosure provides methods for treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 ECD polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 108; SEQ ID NO: 109; SEQ ID NO: 130, SEQ ID NO: 157, SEQ ID NO: 190 and SEQ ID NO: 437.

[0059] In embodiments, the disclosure provides a method for treatment of pulmonary' arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158- 189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431.

[0060] In some embodiments, the ALK6 ECD comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,1902004-0002-004-W0197%, 98%, 99%, or 100% identical to SEQ ID NO: 90. In some embodiments, the ALK6 ECD 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 SEQ ID NO: 286.

[0061] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising an ALK6 extracellular domain (ECD) polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence selected from SEQ ID NO: 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277 and 283.

[0062] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein composing: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence selected from SEQ ID NO: 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277 and 283.

[0063] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein composing: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence selected from SEQ ID NO: 90, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425 and 431.

[0064] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein composing: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence according to SEQ ID NO: 286, In some embodiments, the polypeptide binds BMP6, BMP7 and / or BMP 10. In some embodiments, the fusion protein further comprises a linker sequence. In some embodiments, the fusion protein further comprises a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the heterologous1902004-0002-004-W01sequence is a Fc sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107. In some embodiments, the Fc sequence comprises the amino acid sequence of SEQ ID NO: 106.|0065] In certain embodiments, the disclosure provides, a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence 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 SEQ ID NO: 203-212, 214-217, 219-222, 224-227, 229-232, 234-241, 243-246, 248-251, 253-256, 258-261, 263-266, 268-271, 273-276, 278-282 and 284. In certain embodiments, the disclosure provides, a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence composes 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 SEQ ID NO: 91, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432. In certain embodiments, the disclosure provides, a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence 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 SEQ ID NO: 287. The fusion protein of claim 75-77, wherein the linker sequence is according to SEQ ID NO: 6. in some embodiments, the heterologous sequence is an Fc sequence according to SEQ ID NO: 106. In some embodiments, the ALK6 ECD polypeptide is present as a homodimer.

[0066] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD); a linker sequence; and an Fc domain sequence; wherein the AEK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 286, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained binding to BMP10. In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to SEQ ID NO: 49. in some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt)1902004-0002-004-W01Fc fusion protein, in some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 7.2 for BMP10 binding. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 4.8 for BMP7 binding.|0067] In certain embodiments, the disclosure provides a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD); a linker sequence; and an Fc domain sequence; wherein the fusion protein sequence comprises or consists of 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 an ALK6 fusion protein sequence of SEQ ID NO: 287, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding.

[0068] In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to SEQ ID NO: 49. In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein. In some embodiments, tlie ALK6 fusion protein demonstrates an nM IC50 value of about 7.2 for BMP 10 binding. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 4,8 for BMP7 binding. In some embodiments, the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding. In some embodiments, tire ALK6 fusion protein demonstrates BMP10 binding comparable to SEQ ID NO: 49. In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 7.2 for BMP10 binding. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 4,8 for BMP7 binding. In some embodiments, the linker sequence comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments, the Fc sequence comprises an amino acid sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

[0069] In certain embodiments, tire disclosure provides pharmaceutical compositions comprising a fusion protein provided herein. In certain embodiments, the disclosure provides a pharmaceutical composition comprising a fusion protein disclosed herein; and, at least one pharmaceutical acceptable carrier or buffer. In some embodiments, the ALK6 ECD polypeptide is present as a homodimer.

[0070] In certain embodiments, the disclosure provides the use of a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein for treatment of vascular inflammation1902004-0002-004-W01in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising: an ALK6 extracellular domain (ECD); a linker sequence; and an Fc domain sequence; wherein the ALK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 286, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP10 binding.

[0071] In certain embodiments, the disclosure provides use of a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising: an ALK6 extracellular domain (ECD); a linker sequence; and an Fc domain sequence; wherein the ALK6 Fc fusion protein sequence comprises or consists of 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 an ALK6 Fc fusion sequence of SEQ ID NO: 287, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding,

[0072] In certain embodiments the disclosure provides use of a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising: an ALK6 extracellular domain (ECD); a linker sequence; and, an Fc domain sequence; wherein the ALK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 437, therein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding. In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to SEQ ID NO: 49. In some embodiments, the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 7.2 for BMP10 binding. In some embodiments, the ALK6 fusion protein demonstrates an nM IC50 value of about 4,8 for BMP7 binding. In some embodiments, the vascular inflammation is pulmonary arterial hypertension (PAH).1902004-0002-004-W01

[0073] BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1A and 1B show SDS-PAGE gels for a number soluble ALK6 Fc fusion proteins purified using protein A chromatography (SEQ ID NO: 46-50, 70, 72, 74, 76, 84 and 85) and the cleavage fragment indicating a protease cleavage site present in SEQ ID NO: 49, 47 and 76. See Example 1.

[0075] Figure 2A and 2B show SDS-PAGE gels for a number of soluble ALK6 Fc fusion protein variants using purified using protein A chromatography and demonstrating no cleavage fragments and indicating removal of the protease cleavage site and reduced aggregation for some variants in the non-reduced lanes of the gel. Figure 2A shows the quantity of soluble ALK6 Fc fusion protein generated in 200 ml of cell culture demonstrating significantly improved expression for some of the variant (e.g. SEQ ID NO: 60 and 62). Those variants have point mutations replacing two histidine residues (aa22 and aa23) with serine and glycine, (SEQ ID NO: 60 also has the lysine at position 20 replaced with a tyrosine) and when compared to the expression of SEQ ID NO: 46, indicates doing so provides dramatic improvement in the expression level of those fusion proteins. See Example 2.

[0076] Figure 2C shows SDS-PAGE gels for a number of soluble ALK6 Fc fusion protein variants using purified using protein A chromatography and demonstrating no cleavage fragments and indicating removal of the protease cleavage site and reduced aggregation in the non-reduced lanes of the gel. The gel also shows the quantity of soluble ALK6 Fc fusion protein generated in 10ml of cell culture demonstrating significantly improved expression for some of the variants (e.g., SEQ ID NO: 234 and SEQ ID NO: 243. Those variants have point mutations replacing isoleucine (I) at aa33 and serine (S) at aa35 with threonine (T) and isoleucine (I), respectively. Those point mutations on either side of the cystine residue (at position 34) introduce a glycosylation site dramatically improving folding and expression of the fusion protein. See Example 2.

[0077] Figure 3A shows BMP4 and BMP 10 binding for soluble ALK6 Fc fusion proteins of this disclosure. The binding data demonstrates two of the variants (SEQ ID NO: 46 and 52) retain BMP4 and BMP 10 ligand binding (as compared to the ALK6 wt sequence, which binds BMP2, BMP4, BMP6, BMP7, BMP 10 and GDF5, GDF6 and GDF7), but that SEQ ID NO: 55 no longer binds BMP 10 indicating the LGL to MKY change at positions 59, 60 and 61, respectively, is responsible for the loss of binding. See Example 3.1902004-0002-004-W01

[0078] Figure 3B shows ligand binding for soluble ALK6 Fc fusion proteins of this disclosure, wherein NB indicates no binding and a blank box in the table means the ligand binding was not tested. SEQ ID NO: 89 demonstrated a loss of BMP10 binding (as compared to ALK6 wt sequence) and which contains the same G60K point mutation as SEQ ID NO: 55 (which also has a loss of BMP 10 binding and a reduction in BMP7 binding) indicating that point mutation is responsible for the change in ligand binding for BMP 10, SEQ ID NO: 89 (and SEQ ID NO:91 and 93) also demonstrates a retention of BMP7 binding (as compared to ALK6 wt sequence), while SEQ ID NO: 55 only demonstrates weak binding to BMP7. See Example 3.

[0079] Figure 4 shows an IC50 test of SEQ ID NO: 87 in a BMP Responsive Luciferase Assay for the BMP2, BMP4, BMP6 and BMP10 ligands. See Example 4.

[0080] Figure 5 shows an IC50 test of SEQ ID NO: 70 in a BMP Responsive Luciferase Assay for the BMP2, BMP4, BMP6 and BMP10 ligands. See Example 4.

[0081] Figure 6 shows reduction of fasting blood glucose, fasting serum insulin, oral glucose tolerance at day 21 and body weight change with a soluble ALK-6 Fc fusion protein on this disclosure comprising SEQ ID NO: 86 in a STZ induced diabetic mouse model. The data demonstrate the ALK6 ligand trap of this disclosure reverse STZ-induced hyperglycemia and improves glucose excursion without altering fasting serum insulin See Example 5.

[0082] Figure 7A shows the effects of an ALK6 Fc fusion protein of this disclosure comprising SEQ ID NO: 286 in a rat model for PAH. Measurements are provided for mPAP, RVSP, RV, LV+S and RVHI=RV / LV+S. (mPAP) mean pulmonary arterial pressure over entire cycle, wherein lower in treated group lowers pulmonary arterial pressure; (RVSP) right ventricular systolic pressure; (RV) weight of right ventricle- high blood pressure causes right ventricular hypertrophy (right sided heart failure); (LV+S) weight of left ventricle plus the septum; and, (RVHI=RV / LV+S) right ventricular hypertrophy index or Fultons index, demonstrates right sided ventricular hypertrophy only. G1 - Normal + vehicle; G2 - Model + vehicle; G3 - Model + sotatercept; G4 - Model + ALK6 Fc fusion protein of this disclosure comprising SEQ ID NO: 286. See Example 9.

[0083] Figure 7B shows the effects of an ALK6 Fc fusion protein of this disclosure comprising SEQ ID NO: 286 in a rat model for PAH demonstrating a decrease in pulmonary arterial wall thickness % (the fraction of the vessels external diameter that is occupied by the muscular wall). Also shown is H& E staining of lung tissue demonstrating the pulmonary arterial1902004-0002-004-W01thickness across the four groups (G1 - Normal + vehicle; G2 - Model + vehicle; G3 - Model + sotatercept; G4 - Model + ALK6 Fc fusion protein of this disclosure comprising SEQ ID NO: 286). See Example 9.

[0084] Figure 8 shows pictures from three SDS-PAGE gels with reduced and not reduced lanes with the ALK6wt-Fc fusion protein (SEQ ID NO:49), left gel, variant construct SEQ ID NO: 70 (middle gel) and variant construct SEQ ID NO: 287 (right gel), wherein SEQ ID NO: 49 is aggregated and has a protease cleavage site in the c-terminus (indicated on gel); SEQ ID NO: 70 remains aggregated (multiple bands above the * band of the fusion protein) but is no longer cleaved; and SEQ ID NO: 287 is no longer aggregated or cleaved. See Example 1.

[0085] Figure 9 shows the reduced and non-reduced SDS-PAGE gels with a number of ALK6 variant constructs demonstrating those constructs are not aggregated or cleaved. See Example lb.

[0086] Figure 10 shows the ligand binding (BMP2, BMP7, BMP10, BMP4 and BMP6) for SEQ ID NO: 287 wherein SEQ ID NO: 287 is a weak and partial inhibitor of BMP2 signaling. See Example 4.

[0087] DETAILED DESCRIPTION OF THE DISCLOSURE

[0088] Overview

[0089] This disclosure relates to soluble bone morphogenetic protein (BMP) receptor type IB polypeptides comprising an extracellular domain of ALK6 (activin receptor-like kinase 6) and variants thereof (“ALK6 polypeptides”), soluble polypeptides, dimeric complexes, methods of making and uses thereof. Endogenous ALK6 is a member of the TGF-beta superfamily wherein signaling in vivo is mediated by heteromeric complexes of type I and type II serine / threonine kinase receptors, which phosphorylate and activate downstream SMAD proteins (e.g., SMAD proteins 1, 2, 3, 5, and 8) upon ligand stimulation. See, e.g., Massague (2000) Nat. Rev. Mol. Cell Biol. 1:169-178. These type I and type II receptors are transmembrane proteins, composed of a ligand-binding extracellular domain (ECD) with cysteme-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine / threonine kinase specificity. In general, type I receptors mediate intracellular signaling while the type II receptors are required for binding TGF-beta superfamily ligands. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors.1902004-0002-004-W01

[0090] Ligands for ALK6 are BMPs which are members of the TGF-beta superfamily, and exhibit broad spectra of biological activities in various tissues, including bone, cartilage, blood vessels, endothelia, heart, kidney, neurons, liver and lung. The BMPs and GDFs together form a family of cysteine-knot cytokines sharing the characteristic fold of the TGF-beta superfamily. See, e.g., Rider et ai. (2010) Biochem J., 429(1): 1-12. This family includes, for example, BMP2, BMP4, BMP5, BMP6, BMP7, BMP2a, BMP3, BMP3b (also known as GDF10), BMP8, BMP8a, BMP8b, BMP9 (also known as GDF2), BMP 10, BMP 11 (also known as GDF11), BMP12 (also known as GDF7), BMP13 (also known as GDF6), BMP14 (also known as GDF5), BMP 15, GDF1, GDF3 (also known as VGR2), GDF8 (also known as myostatin), GDF9, and GDF15. Besides the ability to induce bone formation, which gave the BMPs their name, the BMP / GDFs display morphogenetic activities in the development of a wide range of tissues. BMP / GDF homo- and hetero-dimers interact with combinations of type I and type II receptor dimers to produce multiple possible signaling complexes, leading to the activation of one of two competing sets of SMAD transcription factors. BMP / GDFs have highly specific and localized functions. These are regulated in a number of ways, including the developmental restriction of BMP / GDF expression and through the secretion of several specific BMP antagonist proteins that bind with high affinity to the cytokines.

[0091] In addition, BMP signaling has also been shown to promote vascular inflammation which is an important contributor to several diseases including atherosclerosis, Alzheimer’s disease multiple sclerosis, and several retinopathies. The endothelium is defined as the thin internal cell layer of blood and lymphatic vessels that are derived from mesodermal lineage. BMP signaling has been shown to lead to endothelial mesenchymal transformation or EMT leading to dysfunctional vasculature and pathological sequela. Healthy endothelium plays an essential role mainly in providing nutrients and oxygen to organs, regulating antioxidant factors, modulating the response to infection, controlling the vascular tone, and the formation of new blood vessels. This last process, named angiogenesis, consists of the formation of new blood vessels from the pre-existing ones as a result of angiogenic growth factor induction. In adulthood, the endothelium is quiescent, meaning that the balance between pro- and anti-angiogenic modulators ensures the stability of blood vessel. However, angiogenesis can be reactivated under either physiological (wound healing, placentation, menstruation) or pathological conditions (tumorigenesis, stroke, inflammation, rheumatoid arthritis, etc.). Among the factors contributing to vascular development and homeostasis, vascular endothelial growth factor (VEGF) is a key endothelial cell activator, VEGF triggers proliferation toward1902004-0002-004-W01VEGF gradient, survival, and permeability of endothelial cell. To ensure the stability of the new formed-vessel, a step of vessel maturation is required through quiescent factors control. |0092] Angiogenesis plays a crucial role in numerous pathological conditions such as inflammation and tumorigenesis. In addition, regenerative medicine for vascular systems has attracted much attention as a potential means of eliminating the vascular-system defects accompanying diabetes and other diseases. Provided herein are molecules that bind selectively to BMP for the treatment of inflammation and vascular dysfunction.

[0093] Pulmonary hypertension (PH) is an incurable condition with a high mortality rate is defined by a resting mean pulmonary arterial pressure > 20 mmHg in association with normal pulmonary arterial wedge pressure (< 15 mmHg) and pulmonary vascular resistance (> 3 Wood unit) measured by right heart catheterization. There are more than 30 types of pulmonary hypertension that have been classified by the WHO (World Health Organization) into five groups. Among them, PAH is a rare disease with an estimated prevalence ranging from 10 to 52 cases per million. PAH is characterized by a pulmonary’ vascular remodeling yvith an hypertrophy of the media, adventitial fibrosis, thrombotic lesions, plexiform lesions, and perivascular infiltration of inflammatory cells. Although the pathogenic mechanisms are not well understood, vasoconstriction, proliferation, thrombosis, and inflammation in the lung microcirculation seem to drive the progression of the disease. The resulting increase in pulmonary vascular resistance leads to right ventricular overload and eventually right heart failure and death. In 2000, genetic analysis of families with heritable PAH identified heterozygous germline mutations in BMPR2. Further investigation showed that BMPR2 is the most frequently mutated gene as BMPR2 mutations are found in 80% of familial PAH. However, the penetrance is incomplete and the mechanism through which these mutations increase the risk of developing PAH is still unclear. Since then, other less frequent mutations have been identified within this signaling pathway (in ACVRL1, ENG, SMAD9, BMP9 / GDF2, and BMP 10). The first BMP9 / GDF2 mutation in PAH yvas published in 2016 as a case report of a homozygous nonsense BMP 9 mutation in a child with PAH, while the parents with the same heterozygous mutation had no PAH symptoms. Since then many heterozygous mutations in BMP9 / GDF2 have been found associated yvith PAH. A truncating mutation and a predicted loss of function variant were also found in BMP 10 in two severely affected PAH patients. Some BMP9 mutations have recently been associated with impaired processing and secretion and reduced activity, while other BMP9 mutations had no functional consequences. Biochemical and functional characterizations of BMP 10 mutations have not1902004-0002-004-W01been reported yet. However, due to the role of BMP 10 in heart morphogenesis, it is possible that these mutations could cause cardiac problems that could increase the risk of developing pulmonary hypertension. Indeed, one of the rare patients with BMP 10 mutation presents features of congenital heart disease. As BMP9 and BMP10 are dimeric proteins, it is important to keep in mind that heterozygote mutations in BMP9 / GDF2 or BMP 10 could have a dominant negative effect on BMP9 or BMP10 homo- and heterodimers.

[0094] Provided herein in embodiments are BMP trap molecules (‘ BMP antagonists’’) comprising the soluble ALK6 polypeptides of this disclosure, which bind BMP ligands and prevent their binding to endogenous transmembrane receptors thus down regulating the BMP signaling pathway. Inhibiting selective BMPs (those that naturally bind to ALK-6, provided above, or those through point mutation have been engineered to bind by ALK6 variants of this disclosure), are provided herein as treatment for inflammation and vascular dysfunction. ALK6 ligands including BMP 2, 4, 5, 6, and 7 are associated with vascular inflammation, inhibiting any those while not inhibiting / binding to BMP-9 and / or BMP- 10 may participate in quiescence of endothelia cells. This down regulation of selected BMP signaling pathways inhibits, for example, the Smad 1 / 5 / 8 cascade alleviating certain vascular inflammation disorders such as retinopathy. In embodiments, selective inhibition of BMP molecules may shift or restore a balance so that the BMP molecules not bound by the ALK-6 polypeptide of this disclosure (e.g. BMP 9 and in certain cases BMP9 and 10 ) are now free to bind their target receptor without competition from other BMP ligands (e.g. BMP 2, 4, 5, 6, and 7). In certain embodiments, BMP9 endothelia quiescent activity is increased by inhibiting competing ligands for common receptor components BMPRI1 for example. As used herein, a “trap molecule” sequesters the respective ligand (e.g. BMPs) before it can interact with the endogenous receptor and thus inhibiting the signal transduction pathway. The soluble ALK6 polypeptides, when fused to a heterologous domain (e.g., Fc domain or IgG hinge region) (“fusion polypeptide”) form homodimers. In embodiments, any sequence that will form one or more disulfide bonds can be used to form the homodimers.

[0095] Provided in certain embodiments are methods for the treatment of vascular inflammation, comprising administering the soluble ALK6 polypeptides of this disclosure to a subject in need thereof. In certain embodiments the method for the treatment of vascular inflammation comprises administering a pharmaceutical composition to a subject in need thereof, 'herein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence of1902004-0002-004-W01this disclosure. In embodiments, the Fc sequence is not full length but just long enough to for the fused ALK6 ECD polypeptides to form homodimers.|0096] Applicants surprisingly found that maintaining a glycine (G) residue at position 60, according to SEQ ID NO: 1, provides an ALK6 ECD variant that binds BMP10 (even with one or more point mutations or a deletion of C- or N-terminal residues). Importantly, mutations at this position can be introduced to remove BMP10 binding wherein other ligands (e.g., BMP2, BMP4) are bound by the ALK-6 trap molecules leaving BMP9 and BMP 10 available to bind to their receptor and activate anti-inflammatory pathways. ALK6 ECD variants, such as SEQ ID NO: 55 and SEQ ID NO: 89, that had a point mutation at that position (e.g., G60K) lost BMP10 binding as compared to the ALK6 wt ECD sequence (SEQ ID NO: 46). See Figure 3B. Additional point mutations in the SEQ ID NO: 90 background providing SEQ ID NO: 286 ECD also fully inhibited BMP10 signaling as fusion protein SEQ ID NO: 287. See Figure 10. In certain embodiments, the ALK6 fusion proteins of this disclosure bind BMP 10 (variants with glycine at amino acid position 60). in certain other embodiments, the ALK6 fusion proteins of this disclosure do not bind BMP10 (e.g, contain a point mutation at amino acid position such as G60K.

[0097] Provided in certain embodiments are methods for treating a vascular inflammation disorder, comprising administering the soluble ALK6 polypeptides of this disclosure to a subject in need thereof. In embodiments, the vascular inflammation disorder is pulmonary arterial hypertension (PAH). In certain embodiments the method for treating the vascular inflammation disorder comprises administering a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence of this disclosure. In certain embodiments the soluble ALK6 ECD-Fc fusion protein is SEQ ID NO: 287, or a sequence having at least 90% identity to SEQ ID NO: 287.

[0098] Definitions

[0099] The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below or elsewhere in the specification to provide additional guidance to the practitioner in describing the compositions and methods of the disclosure and how to make and use them. The scope or meaning of any use of a term will be apparent from the specific context in which it is used.1902004-0002-004-W01

[0100] The term “sequence similarity,” in all its grammatical forms, refers to the degree of identity or correspondence between nucleic acid or amino acid sequences that may or may not share a common evolutionary origin,

[0101] " Percent (%) sequence identity" with respect to a reference polypeptide (or nucleotide) sequence is defined as the percentage of amino acid residues (or nucleic acids) in a candidate sequence that are identical to the amino acid residues (or nucleic acids) in the reference polypeptide (nucleotide) sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid (nucleic acid) sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U. S. Copyright Office, Washington D C., 20559, where it is registered under U. S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0102] “ Antagonize”, in all its grammatical forms, refers to the process of inhibiting a protein and / or gene (e.g., by inhibiting or decreasing that protein’s gene expression or by inducing an active protein to enter an inactive state) or decreasing a protein’s and / or gene’s activity. As used herein the ALK6 polypeptides are referred to as antagonists for the endogenous ALK6 transmembrane receptor signaling pathway wherein the ALK6 polypeptides bind and sequester their endogenous BMP ligand.

[0103] The terms "about" and "approximately" as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is ± 10%. Alternatively, and particularly in biological systems, the terms "about" and "approximately"1902004-0002-004-W01may mean values that are within an order of magnitude, preferably < 5 -fold and more preferably < 2-fold of a given value.

[0104] Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Accordingly, unless indicated to the contrary', the numerical parameters set forth in the following description and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0105] The terms "a" and "an" include plural referents unless the context in which the term is used clearly dictates otherwise. Tire terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two or more specified features or components with or without the other. Thus, the term “and / or" as used in a phrase such as " A and / or B" herein is intended to include " A and B," " A or B," " A" (alone), and " B" (alone). Likewise, the term "and / or" as used in a phrase such as " A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0106] The term “or” is used herein in the inclusive sense, i.e., equivalent to “and / or” unless the context clearly requires otherwise.

[0107] The use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” is not intended to be limiting, and means that at least the named compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named.

[0108] Tire terms "treatment", "treating", “alleviating” and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect, and may also be used to refer to improving, alleviating, and / or decreasing the severity of one or more clinical complication of a condition being treated. The effect may be prophylactic in terms of completely or partially delaying the onset or recurrence of a disease, condition, or1902004-0002-004-W01complications thereof, and / or may be therapeutic in terms of a partial or complete cure for a disease or condition and / or adverse effect attributable to the disease or condition. " Treatment" as used herein covers any treatment of a disease or condition of a mammal, particularly a human. As used herein, a therapeutic that "‘prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of the disease or condition, relative to an untreated control sample.

[0109] In general, treatment or prevention of a disease or condition as described in the present disclosure is achieved by administering one or more soluble ALK6 polypeptides of the present disclosure in an "effective amount". An effective amount of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A "therapeutically effective amount" of an agent of the present disclosure may vary- according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0110] The term “vascular inflammation” has its usual meaning in the art, and refers to a progressive inflammatory condition characterized by the vascular infiltration by white blood cells, build-up of sclerotic plaques within vascular walls, and in particular, arterial walls. Vascular inflammation is a key process for the initiation and progression of atherosclerosis and vascular disease.

[0111] The phrase “conditions associated with vascular inflammation” includes any disease where vascular inflammation is known to play a key role in pathogenesis, such as coronary artery disease, aortic and other vascular aneurysms, carotid plaques, peripheral arterial disease.

[0112] Also, in describing the embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

[0113] Bone Morphogenetic Protein (BMP) Receptor Type IB Polypeptides

[0114] The present disclosure generally relates to soluble ALK6 polypeptides, variants thereof, compositions, and uses thereof (e.g., treating, preventing or reducing the progression rate and / or severity of vascular inflammation disorders). Such vascular inflammation disorders include, but not limited to, pulmonary hypertension (PH), pulmonary arterial hypertension right1902004-0002-004-W01sided heart failure, pulmonary arterial hypertension (PAH), cardiovascular disease, cardiac calcification, atrial fibrillation, diabetic or primary cardiomyopathy (DCM), myocardial hypertrophy, cardiac hypertrophy, myocardial fibrosis, vasculitis, Giant cell arteritis, Granulomatosis with polyangiitis (GPA), Buerger's disease, IgA vasculitis, Kawasaki disease, Takayasu arteritis, Fibromuscular dysplasia (FMD), Primary lymphedema, Secondary lymphedema, diabetic ulcers, and diabetic nephropathy. As used herein the term “AEK6 polypeptide” refers to the extracellular domain of human ALK6 provided for example in SEQ ID NO: 1, as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a useful activity.|0115] Numbering of amino acids for all ALK6-related polypeptides described herein is based on the numbering of the human ALK6 processed (mature) extracellular domain (ECD) human protein sequence provided below (SEQ ID NO: 1), unless specifically designated otherwise.KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHR(SEQ ID NO: 1)

[0116] The C -terminal “tail” of the extracellular domain is indicated by single underline in SEQ ID NO: 1 (above). In certain embodiments the ALK6 ECD sequence with the “tail” deleted (a A14 sequence or A13 sequence) (“SEQ ID NO: 4 variant”) is as follows:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPP (L) (SEQ ID NO: 4)|0117] In certain embodiments the 14 amino acid deleted C terminal tail sequence is replaced with VVIGPFFDGSIR (SEQ ID NO: 2) providing a variant ALK6 ECD polypeptide (“SEQ ID NO: 11 variant”) as follows:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPVVIGPFFDGSIR(SEQ ID NO: 11)

[0118] In certain embodiments the C-tenninus tail is further deleted for a total of 30 (SEQ ID NO: 439) amino acids and the amino acid deleted C terminal tail sequence is replaced with RTNLCNQYLQPTLPPWIG (SEQ ID NO: 195) providing a variant ALK6 ECD polypeptide (“SEQ ID NO: 156 variant”) as follows:1902004-0002-004-W01KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPI PHQRRS I ECCRTNLCNQYLQPTLPPVVIG

[0119] In certain embodiments the C-terminus tail is further deleted for a total of 30 amino acids (SEQ ID NO: 439) and the amino acid deleted C terminal tail sequence is replaced with TNLCNQYLQPTLPPVVIGPFFDGSIR (SEQ ID NO: 438) providing a variant ALK6 ECD polypeptide (“SEQ ID NO: 425 variant”) as follows:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPI PHQRRS I ECCTNLCNQYLQPTLPPVVIGPFFDGSIR

[0120] In certain other embodiments, a seven amino acid portion of the “tail” sequence is deleted (a A7 sequence) from SEQ ID NO: 1 (“SEQ ID NO: 69 variant”), providing the following sequence:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPI PHQRRS IECCTERNECNKDLHPTLPPLKNRDFV (SEQ ID NO: 69)

[0121] In certain other embodiments provided herein the last two histidine amino acids of the “tail” sequence from SEQ ID NO: 1 (“SEQ ID NO: 80 variant”) are deleted providing an ALK6 ECD polypeptide having the sequence:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPI PHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPI__R(SEQ ID NO: 80)

[0122] In certain other embodiments provided herein the mutations K20Y; H22S; _22’A (inserted between aa22 and aa23) H23G are inserted into SEQ ID NO: 69 (“SEQ ID NO: 90 variant”) providing the following sequence:KKEDGESTAPTPRPKVLRCYCSAGHCPEDSVNNICSTDGYCFTMIEEDDSGLPWTS GCLGLEGSDFQCRDTPI PHQRRS IECCTERNECNKDLHPTLPPLKNRDFV

[0123] In certain other embodiments, a seven amino acid portion of the “tail” sequence is deleted (a A7 sequence) from SEQ ID NO: 1 (“SEQ ID NO: 113 variant”), and an arginine amino acid added between aa22 and aa23, providing the following sequence:KKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLGLEGSDFQCRDTPI PHQRRS IECCTERNECNKDLHPTLPPLKNRDFV(SEQ ID NO: 113)1902004-0002-004-W01

[0124] In certain embodiments the ALK6 ECD sequence within the N-terminus is deleted (a A10 sequence, a A13 sequence or a A16 sequence) (“SEQ ID NO: 153 variant”, “SEQ ID NO: 154 variant” or “SEQ ID NO: 155 variant”,) is as follows:|0125] TPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPWTSGCLGLEGSDFQ CRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHR (SEQ ID NO: 153)

[0126] PKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPWTSGCLGLEGSDFQCRD TPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHR (SEQ ID NO: 154)

[0127] LRCKCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPWTSGCLGLEGSDFQCRDTPI PHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHR (SEQ ID NO: 155)

[0128] In certain embodiments, the ALK6 polypeptide comprises a combination of a modified version of SEQ ID NO: 1 (i.e., the extracellular domain of “wild-type” or naturally occurring BMP antagonist). In embodiments, the wild-type ALK-6 does not include the C -terminal sequence of SEQ ID NO: 1, such as that shown in SEQ ID NO: 4. In embodiments, the ALK6 polypeptide comprises a modified version of SEQ ID NO: 1 wherein a seven amino acid portion of the “tail” sequence is deleted (SEQ ID NO: 69) or wherein two histidine amino acids at positions 111 and 112 of the ALK6 polypeptide ECD sequence are deleted (SEQ ID NO: 80). In certain embodiments, the ALK6 polypeptide comprises SEQ ID NO: 11 wherein the fourteen (14) amino acid “tail” deleted sequence is replaced with SEQ ID NO: 2. In certain embodiments, the ALK6 polypeptide comprises SEQ ID NO: 156 wherein a thirty (30) amino acid “tail” deleted sequence is replaced with SEQ ID NO: 2. In certain embodiments, the ALK6 polypeptide comprises SEQ ID NO: 425 wherein a thirty (30) amino acid “tail” sequence is replaced with SEQ ID NO: 438. In certain embodiments, the ALK6 polypeptide has the N terminus deleted or truncated, by 10 (SEQ ID NO: 153), 13 (SEQ ID NO: 154) or 16 (SEQ ID NO: 155) amino acid positions. As described in more detail below, any of these sequences (e.g., SEQ ID NO: 1, 4, 11, 69, 80, 113, 153, 154, 155, 156 or 425) can be modified to alter and / or optimize ligand binding and / or to remove undesirable properties (e.g,, protease cleave site(s) or aggregation).

[0129] Accordingly, a general formula for an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 1, Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino1902004-0002-004-W01acid 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 ALK6 ECD of SEQ ID NO: 1.

[0130] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 4. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 4.

[0131] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 11. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 11.

[0132] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 69. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 69.

[0133] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 80. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 80.

[0134] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 90. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 90.

[0135] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 113. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 113.

[0136] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 153. Therefore ALK61902004-0002-004-W01polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 153.|0137] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 154. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 154.

[0138] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 155. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 155.

[0139] In embodiments, an active portion (e.g., ligand binding) of ALK6 is a polypeptide that comprises, consists essentially of, or consists of SEQ ID NO: 156. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 156.

[0140] Provided herein are specific point mutations or point deletions within any of the above disclosed SEQ ID NO: 1, 4, 11, 69, 80, 90, 113, 153, 154, 155 or 156. Those exemplified mutations and / or deletions and / or addition are represented in SEQ ID NO: 3, 5, 79, 81, 82, 83, 108, 109, 130, 157, 190 or 437. Provided herein are ALK6 ECD sequences selected from any sequence according to SEQ ID NO: 3, 5, 79, 81, 82, 83, 108, 109, 130, 157, 190 or 437.

[0141] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 3. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 5. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 79. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 81. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 82. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 83. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 108. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 109. In certain1902004-0002-004-W01embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 153. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 154. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 155. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 156. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 130. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 157. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 190. In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 437.

[0142] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 3 as shown below using standard three-letter amino acid abbreviations:I SI - Lys2 - Glus - Aspr - Glys - Glue - Ser? - Thrs - Alaa - Prow - Thru - Pror 2 - Argi3 -Proi4 - Xaais - Valis - Leui? - Argis - Cysi9 - Xaa2o - Cys2i - Xaa?.?. - Xaa?,3 -- His24 - Cys?.5 - Pro?,6 - Xaa?,7 -- Aspzs - Xaa?,9 - Xaaso - Asnsi - Asm? - Xaa33 - CyS34 - Xaass - Thrss - Xaaa? - Gly?,« - Xaa39 - Cys o - Phe i - Xaa42 - Xaa43 - Ile44 - Glurs - Glurs - Asp? - Asprs - Xaa49 - Glyso - Xaasi - Xaas2 - Xaa53 - Xaa$4 - Xaass - Serss - Glys? - Cysss - Xaasa - Xaaso - Xaasi - Glus? -- Gly63 - Serg4 - Aspes - Phess - Gln67 – Cys68 - Xaas - Aspro - Xaan - Pro72 - Xaa?3 - Xaa?4 - Xaars - Xa?6 - Arg?? - Arg?s - Xaa?9 - Ileso - Glusi - Cyss? - Cysss - Xaas4 - Xaass - Xaass - Xaas? - Xaass - Cyss9 - Asn o - Xaasi - Xa 92 - Leu s - Xaaa4- Pro s - Thras- Leua? - Pro98 - Proaa - Xaatoo - Xaaioi - Xaaio2 - Xaaio3 - Xaaio4 - Xaaios - Xaaios - Xaaio? - Xaaios - Xaaios - Xaano - Xaain - Xaam - Xaaiis;wherein Xaa15is K or P;Xaa2o is V, F, K or Y;Xaa22 is G, H or S;Xaa23 is S, H or G;Xaa27 is E or D;1902004-0002-004-W01 Xaa29 is S or A;Xaaso is V or I;Xaas3 is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xaa53 is V or T;Xaa54 is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69 is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76 is Q or L;Xaa79is S or T;1902004-0002-004-W01Xaa84 is T or R;Xaa85 is absent, T or E;Xaa86 is R or N;Xaa87 is N or L;Xaa88 is absent, E or L;Xaa91 is K or Q;Xaa92is D or L;Xaa94 is H or Q;Xaa100 is absent, V or L;Xaa101 is absent, V or K;Xaa102 is absent, I or N;Xaa103 is absent, G or R;Xaa104 is absent, P, D or A;Xaa105 is absent or F;Xaa106 is absent, F or V;Xaa107 is absent or D;Xaa108 is absent or G;Xaa109 is absent, S or P;Xaa110 is absent or I;Xaa111 is absent, R or H;Xaa112 is absent or H; and,Xaa113 is absent or R (SEQ ID NO: 3).

[0143] In embodiments, the ALK6 ECD polypeptide of the fusion protein comprises a substitution selected from K15P, K20Y, K20V, K20F, H22S, H22G, H23G, H23S, E27D, S29A, V301, 133T, S35I, D37N, Y39H, T42A, M431, S49Q, L51E, P52T, V53T, T55A, L59M,1902004-0002-004-W01G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85, R86N, N87L, E88_, K91Q, D92L, H94Q, D104A, D107, or a combination thereof, wherein >_ is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from L59M, G60K, and L61 Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S and H23G. In certain embodiments, Xaa100-Xaa113 of the ALK6 ECD polypeptide according to SEQ ID NO: 3 are absent. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K.

[0144] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 3 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 an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 92, 94, 96, 98, and 100.

[0145] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 5 as shown below using standard three-letter amino acid abbreviations:Ly si - Lys? - Glus - Aspr - Glys - Glus - Ser? - Thrs - Alas - Proio - Thru - Proi 2 - Argis -Prou - Xaais - Valis - Leun - Argis - Cysis - Xaa2o - Cys2i - Xaa22 - Xaa23 - His.-; - Cys25 - Pro26 - Xaa2? - Asp2s - Xaa29 - Xaaao- Asnu - Asns2 - Xaa33 - Cysai - Xaass - Three - Xaas? - Glyss - Xaa39 - Cysio - Phe4i - Xaa42 - Xaa43 - He44 - Glu s - Ghus - Asp? - Asp s - Xaa49 - Glyso - Xaasi - Xaa->2 - Xaass - aas4 - Xaass — Serss — Glys? — Cysss - Xaas9 - Xaaso - Xaasi — G1U62 - Glys3 - Sere* - Aspss - Phess - Gln67 – Cys68 - Xaass - Asp™ - Xaan - Pro?2 - Xaa?3 - Xaa?4 - Xaa?s - Xaa?s - Arg?? - Arg?s - Xaa?9 - Ileso - Glusi - Cys»2 - Cysss - Xaas - Xaass - Xaass - Xaas? - Xaass - Cyss9 - Asnso - Xaasi - Xaa92 - Leu93 - Xaa94- Pro95 - Three - I..eu9? - Pro s - Pro99-Leuioo;wherein Xaa15is K or P;Xaa2o is V, F, K or Y;Xaa22 is G, H or S;Xaa23 is S, H or G;Xaa27 is E or D;1902004-0002-004-W01 Xaa29 is S or A;Xaaso is V or I;Xaas3 is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xaa53 is V or T;Xaa54 is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69 is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76 is Q or L;Xaa79is S or T;1902004-0002-004-W01Xaa84 is T or R;Xaa85 is absent, T or E;Xaass is RorN;Xaass is N or L;Xaa88 is absent, E or L;Xaa91 is K or Q;Xaa92is D or L; and,Xaa94 is II or Q (SEQ ID NO: 5).

[0146] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 5 comprises a substitution selected from K15P, K20Y, K20V, K20F, II22S, H22G, H23G, H23S, E27D, S29A, V30I, I33T, S351, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, 17 IS, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85_, R86N, N87L, E88_, K91Q, D92L, H94Q, or a combination thereof, wherein > is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 5 comprises one or more substitutions selected from L59M, G60K, and L61 Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 5 comprises one or more substitutions selected from K20Y, H22S and H23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K.

[0147] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 79 as shown below using standard three-letter amino acid abbreviations:Lysi - LyS2 - Glus - Asp4 - Glys - Glus - Sen - Thrs - Ala9 - Proio - Thru - Pro:; - Argis -Proi4 - Xaais - Valis - Leun - Argis - Cysi9 - Xaaso - Cyssi - Xaa22 - Xaa2s - IIis24 - Cysss - Pro2s - Xaass - Asp28 - Xaa29 - Xaaso - Asnsi - Asn.32 - Xaass - Cys34 - Xaass - Thrss - Xaass - Glyss - Xaas9 - Cysro - Phe4i - Xaa 2 - Xaa s - Ile44 - Glass - Ghus - Asp47 - Asp48 - Xaa 9 - Glyso - Xaasi - Xaass - Xaass - Xaas4 - Xaass - Serss - Glyss - Cysss - Xaas9 - Xaaso - Xaasi - Gluss - Glyss - Sers - Aspss - Phess - Gln67 – Cys68 - Xaas -- Aspso - Xaa?i - Pro72 - Xaass - Xaa?4 - Xaass - Xaass - Arg77 - Argss - Xaas - Ileso - Glusi -1902004-0002-004-W01Cys82 - Cys83 - Xaa«4 - Xaass - Xaa86 - Xaas? - Xaass -- Cysss - Asnso - Xaasi -Xaa92 - Leu93 - Xaa<a- Pro95 - Three- Leu97 - Pro98 - Pro99-Valioo-Valioi-Ileio2- Glyio3-Proio4-Pheio5-Pheio6-Aspio7-Glyio8-Serio9-Ileiio-Argm;wherein Xaa15is K or P;Xaa2o is V, F, K or Y;Xaa?,?, is G, H or S;Xaa23 is S. H or G;Xaa27 is E or D;Xaa?,9 is S or A;Xaa30is V or I;Xaa33 is I or T;Xaa? 5 is S or I;Xaa37 is D or N:Xaa39 is Y orH:Xaa42is T or A;Xaa43 is M or I;Xaa 9 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xa 53 is V or T;Xaas4 is V or L;Xaa55 is T or A;Xaa.59 is L or M;Xaa60is G or K;1902004-0002-004-W01Xaa61 is L or Y;Xaa69is R or K;Xaa71 is T or S:Xaa73 is I or K;Xaa74is P or A;Xaa75 is H or Q;Xaa76is Q or L;Xaa79is S or T;Xaa84 is T or R;Xaas5 is absent, T or E;Xaa86is R or N;Xaa87 is N or L;Xaa88 is absent, E or L;Xaa9i is K or Q;Xaa92is D or L; and,Xaa94is H or Q (SEQ ID NO: 79).

[0148] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 79 comprises a substitution selected from K15P, K20Y, K20V, K20F, H22S, H22G, H23G, H23S, E27D, S29A, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85_, R86N, N87L, E88_, K91Q, D92L, TI94Q, D104A, D107, or a combination thereof, wherein is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 79 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 79 comprises one or more substitutions selected from K20Y, H22S and H23G. in certain other embodiments, the ALK61902004-0002-004-W01ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K.

[0149] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 79 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 an ALK6 ECD sequence selected from SEQ ID NO: 15-45, 57, 59, 61, 63, 65, and 88.

[0150] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 81 as shown below using standard three-letter amino acid abbreviations:Lysi - Lys2 - Glus - Aspr - Glys - Glue - Sen - Ilirs - Alas - Proio - Thru - Pro - Argi3 -Prou - Xaais - Valis - Leui? - Argis - Cysi9 - Xaa2o - Cys2i - Xaa22 - Xaa23 - His24 - Cys?s - Pro?.s - Xaa?_7 - Aspzs - Xaa29 - Xaaso - Asnsi - Asii32 - Xaass - Cys34 - Xaa.v - Thrss - Xaa37 - GE 38 - Xaass - Cysro - Phe i - Xaa42 - Xaa43 - Ile44 - Ghus - Glms - Asp47 - Asp48 - Xaa49- Glyso - Xaasi - Xaas2 - Xaass - Xaasr - Xaass - Sens - Glys? - Cysss - Xaas9 - Xaaso - Xaasi - Glus?. - Glyss - Sers - Aspss - Phess - Gln67 – Cys68 - Xaas9 - Asp?o - Xaa?i - Pro72 - Xaass - Xaa?4 - Xaass - Xaa?6 - Arg77 - Arg78 - Xa?9 - Ileso - Glusi - Cys82 - Cys83 - Xaas - Xaass - Xaass - Xaas? - Xaass - Cys89 - Asn o - Xaasi - Xa 92 - Leu93 - Xaa94- Pro s ~ Th - Leu? - Pro9 - Pro99 - Leuioo - Lysioi - ASIHO2 - Argios - Aspio4 - Pheios - Valios - Xaaio? - Xaaios - Xaaio9 - Xaauo - Xaam - Xaam - Xaans;wherein Xaa15is K or P;Xaaso is V, F, K or Y;Xaa?.?. is G, H or S;Xaass is S, II or G;Xaa27 is E or D;Xaa?_9 is S or A;Xaaso is V or I;Xa 33 is I or T;Xaa35 is S or I;1902004-0002-004-W01 Xaa37 is D orN;Xaa?9 is Y or H;Xaa42is T or A;Xaars is M or 1;Xaat9 is S or Q;Xaa51 is L or E;Xaa.52 is P or T;Xaass is V or T;Xaa54 is V or L;Xaa.55 is T or A;Xaa59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaars is H or Q;Xaa76 is Q or L;Xaa79is S or T;Xa 84 is T or R;Xaa85 is absent, T or E;Xaa86is R or N;Xa 87 is N or L;1902004-0002-004-W01Xaa88 is absent, E or L;Xaa9i is K or Q;Xaa92is D or L;Xa 94 is H or Q;Xaaio? is absent;Xaa108 is absent;Xaaio9 is absent;Xaano is absent;Xaa111is absent;Xaaii?. is absent; and,XaaiB is absent (SEQ ID NO: 81),

[0151] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 81 comprises a substitution selected from K15P, K20Y, K20V, K20F, H22S, H22G, H23G, H23S, E27D, S29A, V30I, I33T, S351, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85_, R86N, N87L, E88_, K91Q, D92L, H94Q, D104A, or a combination thereof, wherein is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 81 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 81 comprises one or more substitutions selected from K20Y, II22S and H23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K,

[0152] In certain embodiments, the ALK6 ECD polypeptide of the fusion pro tein according to SEQ ID NO: 81 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 an ALK6 ECD sequence selected from SEQ ID NO: 13, 86, 92, 94, 96, 98, 100, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 147, or 149.1902004-0002-004-W01

[0153] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein is selected from a sequence according to SEQ ID NO: 81 comprises an amino acid sequence tliat 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 an ALK6 ECD sequence of SEQ ID NO: 86 wherein amino acid position 60 is a glycine (G) residue.

[0154] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein is selected from a sequence according to SEQ ID NO: 81 comprises an amino acid sequence tliat 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 an ALK6 ECD sequence of SEQ ID NO: 86 wherein amino acid position 60 is other than a glycine (G) residue, suck lysine (K). The point mutation G60K removes BMP 10 binding.

[0155] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 82 as shown below using standard three- letter amino acid abbreviations:Ly si - Lys2 - Glus - Aspr - Glys - Glus - Sen - Thrs - Alas - Proio - Thru - Pro:.- - Argi3 -Proi4 - Xaais - Valis - Leun - Argis - Cysis - Xaaso - Cyssi - Xaa22 - Xaa23 - IIis2 - Cysss - Pro2s - Xaas? - Aspss - Xaa29 - Xaaso - Asm i - Asn32 - Xaa33 - Cyss - Xaass -- Thns - Xaa37 -- Glyss - Xaais - Cysro - Phe4i - Xaa 2 - Xaa43 - Ile44 - Glu s - Ghus - Asp47 - Asp48 - Xaa 9 - Glyso - Xaasi - Xaas2 - Xaass - Xa s4 - Xaass - Sens - Glys? - Cysss - Xaass - Xaaso - Xaasi - G1U62 - GIy$3 - Sers - Aspss - Phess - Gln67 – Cys68 - Xaass - Asp?o - Xaa?i - Pro- ■ - Xaa?3 - Xaa? - Xaass - Xaars - Arg77 - Arg78 - Xaa?s - Ileso - Glusi - Cys 2—Cysss - as4 - Xaass - Xaass - Xaas? - Xaas—C ysss — Asnso - Xaasi - Xaas2 - Leu93 - Xaasi - Press - Thrss- Leus? - Press - Pross - Leuioo - Lysioi - Asmo2 - Argio3 - Aspio4 - Pheios - Valios - Xaaio? - Glyios - Xaaios - Ileno - Xaam - Xaan? - Argus;wherein Xaa15is K or P;Xaaso is V, F, K or Y;Xaa22 is G, II or S;Xaa23 is S, H or G;Xaa27 is E or D;1902004-0002-004-W01 Xaa29 is S or A;Xaaso is V or I;Xaas3 is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xaa53 is V or T;Xaa54 is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69 is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76 is Q or L;Xaa79is S or T;1902004-0002-004-W01Xaa84 is T or R;Xaa85 is absent, T or E;Xaa86 is R or N;Xaas? is N or L;Xaa88 is absent, E or L;Xaa91 is K or Q;Xaa92is D or L;Xaa94 is H or Q;Xaaio? is D or A;Xaaio9 is P or S;Xaa111is absent; and,Xaam is absent (SEQ ID NO: 82).

[0156] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 82 comprises a substitution selected from K15P, K20Y, K20V, K20F, H22S, H22G, H23G, H23S, E27D, S29A, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85, R86N, N87L, E88_, K91Q, D92L, H94Q, D104A, D107, or a combination thereof, wherein > is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 82 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 82 comprises one or more substitutions selected from K20Y’, H22S and H23G, In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K.

[0157] In certain embodiments, the ALK6 ECD polypeptide of tire fusion protein according to SEQ ID NO: 82 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 an ALK6 ECD sequence selected from SEQ ID NO: 67, 73, 75, and 77.1902004-0002-004-W01

[0158] In embodiments, the soluble ALK-6 polypeptide comprises an active portion e.g., ligand binding) of ALK6 according to SEQ ID NO: 83 as shown below using standard three- leter amino acid abbreviations:Lysi - Lys2 - Glus - Asps - Glys - Glue - Ser? - Thrs - Ala9 - Proio - Thru - Pro - Argis -Prou - Xaais - Valis - Leun - Argis - Cysi9 - Xaa2o - Cys2i - Xaa?.?. - Xaa?.3 - His24 - Cys?s - Pro?.s - Xaa?.? - Asp?.s - Xaa?.9 - Xaaso-- Asnsi - Asii32 - Xaass - Cys34 - Xaass - Thrss - Xaas? - Glyss - Xaaso - Cys4o - Phe i - Xaa42 - Xaais - Ile44 - Gla s - Glu46 - Asp47 - Asprs - Xaaso- Glyso - Xaasi - Xaas2 - Xaass - Xaass - Xaass - Sens - Glys? - Cysss - Xaas9 - Xaaso - Xaasi - Glu62 - Glys3 - Sers4 - Aspss - Phess - Gln67 – Cys68 - Xaaso - Asp?o - Xaa?i - Pro72 - Xaa?3 - X a? - Xaa?s - Xaa?s - Arg?? - Argis - Xaa?9 - Ileso - Glusi - Cyss2 - Cysss - Xaass - Xaass - Xaass - Xa s? - Xaass - CyS89 - Asnoo - Xaa9i - Xa 92 - Leu93 - Xaa9i - Pro9s - Thr s- Leuo? - Proos - Pro99 - Leuioo - Lysioi - Asnio2 - Argios - Xaaio - Pheios - Valios - Xaaio? - Glyios - Xaaio - Ileuo - Hism - Hisi 12 - Argus;wherein Xaa15is K or P;Xaa20is V, F, K or Y;Xaa?.?. is G. H or S;Xa 23 is S. H or G;Xaa27 is E or D;Xaa?_9 is S or A;Xaaso is V or I;Xaa33 is I or T;Xaa35 is S or I;Xaas? is D orN;Xaaso is Y or H;Xaas?. is T or A;Xaa43 is M or I;1902004-0002-004-W01 Xaa49 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xaa.53 is V or T;Xaas4 is V or L;Xaa55 is T or A;Xaa.59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69is R or K;Xaa71 is T or S;Xaa73is I or K;Xaa74is P or A;Xaa75is H or Q;Xaa76 is Q or L;Xaa79is S or T;Xaa84is T or R;Xaa85 is absent, T or E;Xaa86is R or N;Xaa87 is N or L;Xaa88 is absent, E or L;Xaa91is K or Q;Xaa92is D or L;Xaa94is H or Q;1902004-0002-004-W01Xaaio4 is D or A;Xaaio? is absent or D; and,Xaa109 is P or S. (SEQ ID NO: 83).

[0159] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 83 comprises a substitution selected from K15P, K20Y, K20F, K20V, H22S, H22G, I-I23G, H23S, E27D, S29A, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85 R86N, N87L, E88__, K91Q, D92L, H94Q, D104A, D107, or a combination thereof, wherein > is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 83 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 83 comprises one or more substitutions selected from K20Y’, H22S and H23G, In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K.

[0160] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 83 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 an ALK6 ECD sequence selected from SEQ ID NO: 12, 14 and 71.

[0161] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 108 as shown below using standard three- letter amino acid abbreviations:Lysi - Lys2 - Glus - Asp* - Glys - Glu6 - Ser? - Thrs - Alas - Proio - Thru - Proi2 - Argu -Proi* - Xaau - Xaaie - Leui? - Argis - Cysis - Xaa2o - Cyssi - Xaa22- Xaa’22-Xaa23 - IIis24 - Cys25 - Pro26 - Xaa27 - Asp28 - Xaa?9 - Xaaso - Asnsi - Asni2 - Xaass - Cyss* - Xaass - Thr36 - Xaa37 - Glyss - Xa s9 -- Cys4o -- Phe*i - Xaa42 - Xaa*3 - Her* - Glu45 — G1U*6 — Asp47 — Asp48 - Xaa*9 — GlyTso - Xaasi - X as2 - Xaass - Xaas4 - Xaass — Sers6 - Glys? - Cysss - Xaas9 - Xaaso - Xaaei - Glu62 - Gives - Ser64 - Aspes - Pheee -Gln67 – Cys68 - Xaas9 - Asp?o - Xaa?i - Pro?2 - Xaa?3 - Xaa?4 - Xaars - Xaa?s - Arg?? - Arg78 - Xaa?9 - Ileso - Glusi -- Cy S82 - Cysss - Xaas4 - Xaass - Xaass - Xaas? - Xaass - Cys89 - Asn o - Xaa i - Xaa?.? - Leu93 - Xaa94 - Pro s - Thr96 - Leu97 - Piws - Pro99 -1902004-0002-004-W01Leu100- Lys101- Asn102- Arg103- Asp104- Phe105- Val106- Xaa107- Xaa108- Xaa109- Xaa110- Xaa111- Xaa112- Xaa113;wherein:Xaa15is K or P;Xaa16is V or I;Xaa20 is V, F, K or Y;Xaa22is G, H or S;Xaa’22 is absent or A- Xaa23 is S. H or G;Xaa27 is E or D;Xaa29is S or A;Xaa30is V or I;Xaa33is I or T;Xaa35 is S or I;Xaa37 is D orN;Xaa39is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49is S or Q;Xaa51 is L or E;Xaa52is P or T;Xaa.53 is V or T;Xaa54is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60is G or K;Xaa61is L or Y;Xaa69 is R or K;Xaa71is T or S;Xaa73is I or K;Xaa74is P or A;Xaa75is H or Q;Xaa76is Q or L;Xaa79is S or T;1902004-0002-004-W01Xaa84 is T or R;Xaa85 is absent, T or E;Xaa86is R or N;Xaas? is N or L;Xaa88 is absent, E or L;Xaa91 is K or Q;Xaa92is D or L;Xaa94 is H or Q;Xaaio? is absent;Xaaios is absent;Xaai 09 is absent;Xaaiio is absent;Xaa111is absent;Xaa111is absent; and,Xaa113is absent (SEQ ID NO: 108)

[0162] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises a substitution selected from K15P, V16I, K20Y, K20V, K20F, H22S, H22G, _22’A, H23G, H23S, E27D, S29A, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85__, R86N, N87L, E88_, K91Q, D92L, H94Q, D104A, or a combination thereof, wherein is a deletion at that position, in certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises one or more substitutions selected from K20Y, H22S and H23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises one or more substitutions selected from K20Y, H22S, 22 ’A and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises one or more substitutions selected from K20Y, II22G, H22K and 1123 S

[0163] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 108 comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%,1902004-0002-004-W0186%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an ALK6 ECD sequence selected from SEQ ID NO: 13, 86, 90, 92, 94, 96, 98, 100, 102, 104, and 110.

[0164] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 109 as shown below using standard three- letter amino acid abbreviations:Lx si - Lys2 - Glus - Asp4 - Glys - Glue - Ser? - Thrs - Alas - Proio - Thru - Proi 2 - Argis -Proi4 - Xaais - Xaais - Leun - Argis - Cysi9 - Xaa?.o - Cys?.i - Xaa - Xaa’22 - Xaa23 - His 4 -- Cys25 - Pro26 - Xaas? - Asp s - Xaa 9 - Xaaso - Asmi - Asn32 - Xaass - Cys34 - Xaass - Thne - Xaas? - Glyss - Xaa?9 - Cysro - Phe i - Xaa42 - Xaa43 - Ile44 - Glu45 - Ghus - Asp47 - Asp s - Xaa49 - Glyso - Xaasi - Xaas 2 - Xaass - Xaas - Xaass ■■■ Sers6 — • Glvs? ■■■ Cysss - Xaass - Xaaso - Xaasi - G1US2 - Gly63 - Sers4 - Asp.-.5 - Phess - Gln67 – Cys68 - Xaas9~~ Asp?o - Xaan - Pro?2 - Xaa73 - Xaa?4 - Xaa?5 - Xaa?6 - Arg?7 - Arg78 - Xaa?9 - Ileso - Glusi - CyS82 - Cysss - Xaas4 - Xaass - Xaass - Xaas? - Xaass - Cysss - Asnso - Xaa9i - Xaa92 Leuss - Xaa94 - Progs - Thr96 - Leu97 Press - Pro99-Valioo- Valioi-Ileio2-Glyio3-Proio4-Pheio5-Pheio6-Aspio7-Glyios-Seno9-Ileiio-Argiii: wherein Xaa15is K or P;Xaa16 is V or I;Xaa2o is V, F, K or Y;Xaa22is G, H or S;Xaa’22 is absent or A;Xaa23is S, H or G;Xaa?7 is E or D;Xaa29is S or A;Xaaso is V or I;Xaa33is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q.1902004-0002-004-W01Xaa51 is L or E;Xaa52 is P or T;Xaas3 is V or T;Xaa54is V or L;Xaa55 is T or A;Xaa59is L or M;Xaa60is G or K;Xaa61 is L or Y;Xaa69is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74is P or A;Xaa75 is H or Q;Xaa76is Q or L;Xaa79is S or T;Xaa84is T or R;Xaa85 is absent, T or E;Xaa86is R or N;Xaa87is N or L;Xaa88 is absent, E or L;Xaa9i is K or Q;Xaa92is D or L; and,Xaa94is H or Q. (SEQ ID NO: 109)

[0165] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 comprises a substitution selected from K15P, V16I, K20Y, K20V, K20F, H22S, H22G, _22’A, H23G, H23S, E27D, S29A, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52, T, V53T, T55A, L59M, G60K, L61Y, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85_, R86N, N87L, E88_, K91Q, D92L, H94Q, D104A, D107, or a combination thereof, wherein >_ is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 comprises one or more substitutions selected from K20Y, H22S and H23G. In certain other embodiments, the ALK61902004-0002-004-W01ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 comprises one or more substitutions selected from K20Y, H22S, __22’A and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 comprises one or more substitutions selected from K20Y, H22G, _22’A and H23S.

[0166] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 109 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 an ALK6 ECD sequence selected from SEQ ID NO: 15-45, 57, 59, 61, 63, 65, and 88.

[0167] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (<?.g., ligand binding) of ALK6 according to SEQ ID NO: 130 as shown below using standard three- letter amino acid abbreviations:

[0168] Lysi - Lys2 - Glus - Aspr - Glys - Glus - Ser? - Thrs - Ala9 - Proio - Thru - Pron - Argis -Prou - Lysis - Xaais -- Leun - Argis - Cysi9 - Xaa?o -- Cys?.i - Xaa?,?,- Xaa’22-Xaa”22-Xaa23 - Xaa’23 - Xaa24 - Cys25 - Pro26 - Xaa27 - Asp28 - Xaa29 - Xaaso- Asmi - Asn32 - Xaa33 - Cys34 - Xaass - Thrv. - Xaa37 - Giyas - Xaa39 - Cys4o - Phen - Xaa 2 - Xaa s - Hem -GIu4s - Glu 46 - Asp47 - Asprs - Xaa49~ Glyso - Xaasi - Xaas?. - Xaas3 - Xaas 4 - Xaass - Serse - Gly57 - Cys58 - Xaa59 - Xaaso - Xaasi - Glus2 - Gives - Sers4 - Aspss - Phess - Gln67 – Cys68 -Xaas9 - Asp?o - Xaa?i - Pro?2 - Xa?3 - Xaa?4 - Xaa?s - Xaa?6 - Arg?? - Arg?s - Xa?9 - Ileso -Glusi - Cys82 - Cys83 - Xaasr - Xaass - Xaase - Xaas? - Xaass- Cyss9 - Asn9o - Xaa9i - Xaa92 - Leu93 - Xaa94 - Pro95 - Thr96- Leu97 - Progs - Pro99 - Leuioo - Lysioi - Asmo?. - Argio3 - Aspio4 - Pheios - V alios - Xaaio? - Xaaios - Xaaio - Xaano - Xaam - Xaan2 - Xaaus;

[0169] wherein Xaa16is V or I;

[0170] Xaa2o is V, F, K, Y, T, or A;

[0171] Xaa22 is G, E, H or S;

[0172] Xaa’ 22 is absent, G, S, or A;

[0173] Xaa”22 is absent or S;

[0174] Xaa23is S, H, G, or L;

[0175] Xaa23' is absent, L or H;

[0176] Xaa24 is H or S;

[0177] Xaa27 is E orD;1902004-0002-004-WO1

[0178] Xaa29 is S or A;

[0179] Xaaso is Vorl;

[0180] Xaa33 is I or T;

[0181] Xaa35 is S or I;

[0182] Xaa37 is D orN;

[0183] Xaa39 is Y or H;

[0184] Xaa42is T or A;

[0185] Xaa43is M or I;

[0186] Xaa49 is S or Q;

[0187] Xaa51 is L or E;

[0188] Xaa52 is P or T;

[0189] Xaa53 is V or T;

[0190] Xaa54 is V or L;

[0191] Xaa55 is T or A;

[0192] Xaa.59 is L or M;

[0193] Xaaso is GorK;

[0194] Xaa61 is L or Y;

[0195] Xaa69 is R or K;

[0196] Xaa71 is T or S;

[0197] Xaa73 is I or K;

[0198] Xaa.74 is P or A;

[0199] Xaa75 is H or Q;

[0200] Xaa76 is Q orL;

[0201] Xaa79 is S or T;

[0202] Xaa84is T or R;

[0203] Xaa85 is absent, T or E;

[0204] Xaa86is R or N;

[0205] Xaas? is N or L;

[0206] Xaa88 is absent, E or L;

[0207] Xaa9iis K or Q;

[0208] Xaa92is D or L;

[0209] Xaa94 is H or Q;

[0210] Xaaio7 is absent;

[0211] Xaaios is absent;1902004-0002-004-W01

[0212] Xaaio9 is absent;

[0213] Xaano is absent;

[0214] Xaa111is absent;

[0215] Xaaii?, is absent; and,

[0216] Xaaii3 is absent. (SEQ ID NO: 130)

[0217] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 130 comprises a substitution selected from K15P, V16I, K20Y, K20V, K20F, K20A, K20A, H22S, H22G, H22E, H22S, _22’A, > 22’___, _22’G, _22’S,. 22”__, _22”S, H23G, H23S, H24S, E27D, S29A, V30I, I33T, I33S, S35I, D37N, Y39H, T42A, M43I, S49Q, L51E, P52T, V53T, T55A, L59M, G60K, L6IY, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, E85T, E85 R86N, N87L, E88 K91Q, D92L, H94Q, D104A, or a combination thereof, wherein is a deletion at that position. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 130 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 130 comprises one or more substitutions selected from K20Y, H22S and H23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, H23G and G60K. In certain embodimen ts, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 130 comprises one or more substitutions selected from K20Y, K20V, K20F, K20A, K20A, H22S, _22’A, _22’_, _22’G, _22’S, _22”_, _22”S and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 130 comprises one or more substitutions selected from K20Y, H22G,..22’A and H23S.

[0218] In certain embodiments, the ALK6 ECD polypeptide of the fusion pro tein according to SEQ ID NO: 130 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 an ALK6 ECD sequence selected from SEQ ID NO: 150, 151 or 152.

[0219] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 157 as shown below using standard three- letter amino acid abbreviations:

[0220] Xaai - Xaa2 - Xaas - Xaa4 - Xaas - Xaas - Xaa? - Xaas - Xaa9 - Xaaio - Xaan - Xaai2 - Xaai3 - Xaau - Xaais - Xaaio - Leun - Argis - Cysi9 - Xaa?.o - Cys2i - Xaa22 - Xaa’22 -1902004-0002-004-W01Xaa~ '22 - Xaa23 - Xaa’23 - Xaa24 - Cys25 - Pro26 - Xa 27 - Asp28 - Xaa29 - Xaa;,o - Asrui - Asi - Xaass - Cys34 - Xaass - Thne - Xaas? - Glyss - Xaa39 - Cys40 - Phci 1 - Xaa42 - Xa 43 - Ile44 -GIU4S - G1U46 - Asp47 - Asp s - Xaa.: 9 - Gly 50 - Xaasi - Xaa.52 - Xaass - Xaasi - Xaass - Serse - Glys7 - Cysss - Xaass - Xaaso - Xaasi - Glass. - Glys3 - Sers4 - Aspss - Phess - Gln67 – Cys68 - Xaass - Asp7o - Xaari - Pro72 - Xa 73 - Xa 74 - Xaa75 - Xaa7s - Arg77 - Arg7s - Xaa?9 - Ileso -Ghi8i - Cyss2 - Cysss - Xaa«4 - Xaass - Xaass - Xaas7 - Xaass - Cysss - Asnso - Xaasi - Xaas2 -Leuss - Xaa94- Pross - Thrss- Leu97 - Pro98 - Pro99 - Xaaioo - Xaaioi - Xaai 02 - Xaaios - Xaann - Xaaios - Xaaios - Xaaio7 - Xaaios - Xaaio9 - Xaano - Xaam - Xaans. - Xaaiis

[0221] wherein: Xaai is K or absent;

[0222] Xaa2 is K or absent;

[0223] Xaas is E or absent;

[0224] Xaa4is D or absent;

[0225] Xaas is G or absent,

[0226] Xaas is E or absent;

[0227] Xaa7is S or absent;

[0228] Xaas is T or absent;

[0229] Xaas is A or absent;

[0230] Xaaio is P or absent;

[0231] Xaai 1 is T or absent;

[0232] Xaai2 is P or absent;

[0233] Xaai 3 is R or absent;

[0234] Xaai 4 is P or absent,

[0235] Xaai 5 is K, P or absent;

[0236] Xaa16is V or absent;

[0237] Xaaso is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;

[0238] Xaa22 is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S;1902004-0002-004-W01

[0239] Xaa’22 is absent, G, S, or A;

[0240] Xaa”22 is absent or S;

[0241] Xaa23is S, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G;

[0242] Xaa'23is absent, L or H;

[0243] Xaa24is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;

[0244] Xaa27 is E or D;

[0245] Xaa29 is S, G or A;

[0246] Xaa30is V, A, G or I;

[0247] Xaa33 is I, S or T;

[0248] Xaa35is S, T, G, A or I;

[0249] Xaa37is D, A, G or N;

[0250] Xaa39is Y, A, G or H;

[0251] Xaa42is T or A;

[0252] Xaa43is M or I;

[0253] Xaa49is S, A, G or Q;

[0254] Xaa51is L, A, G or E;

[0255] Xaa52 is P or T;

[0256] Xaa53is V, A, G or T;

[0257] Xaa54is V, A, G or L;

[0258] Xaa₅₅ is T, G or A;

[0259] Xaa59is L, M, V, F, K, A, R, N, D, C, E, Q, G, H, I, P, S, T, W, or Y;

[0260] Xaa60is G, K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T, W, or Y;

[0261] Xaa61is L, Y, V, F, K, A, R, N, D, C, E, Q, G, H, I, M, P, S, T, or W;

[0262] Xaa69is R or K;1902004-0002-004-W01

[0263] Xaa71is T or S;

[0264] Xaa73 is I or K;

[0265] Xaa74 is P or A;

[0266] Xaa75 is H or Q;

[0267] Xaa76 is Q or L;

[0268] Xaa79is S or T;

[0269] Xaa84is T, R or absent;

[0270] Xaa85 is absent, T or E;

[0271] Xaa86is R, N or absent;

[0272] Xaa87is N, L or absent;

[0273] Xaa88 is absent, E or L;

[0274] Xaa91is K, Q or absent;

[0275] Xaas?. is D, L, Y or absent;

[0276] Xaa94is H, Q or absent;

[0277] Xaa100 is absent, V or L;

[0278] Xaa101 is absent, V or K;

[0279] Xaa102is absent, I or N;

[0280] Xaa103is absent, G or R;

[0281] Xaaio4 is absent, P, D or A;

[0282] Xaa105 is absent or F;

[0283] Xaa106is absent, F, W, Y, N, Q, K, H, D, G, E or V;

[0284] Xaa107is absent, L, M, V, F, K, A, R, N, C, E, Q, G, H, I, P, S, T, W, or Y or D;

[0285] Xaa108is absent, R, T, Q, L, K, W or G;

[0286] Xaa109 is absent, S or P;1902004-0002-004-W01

[0287] Xaa110is absent or I;

[0288] Xaa111is absent, R or H;

[0289] Xaa112 is absent or H; and

[0290] Xaa113is absent or R.

[0291] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 comprises a substitution selected from KI, K2, E3, D4, G5, E6, S7, T8, A9__, P10_, T11_, P12_, R13_, P14_, K15P, K15_, V16__, K20Y, K20V, K20F, K20A, K20R, K20N, K20D, K20C, K20E, K20Q, K20G, K20H, K20I, K20L, K20M, K20P, K20S, K20T, K20W, H22S, H22G, H22E, H22V, H22F, H22K, II22A, H22R, H22N, II22D, II22C, II22Q, H22I, H22L, H22M, H22P, H22T, H22W, H22Y, __22’A, 22'.. 22'G, __22’S, 22'~. __22”S, H23G, H23S, H23V, H23F, H23K, H23A, H23R, H23N, H23D, H23C, H23E, H23Q, H23I, 1123 L, H23M, II23P, II23T, II23W, II23Y, II23G, _23’__, 23 L. 23’11, II24S, II24V, H24F, H24K, H24A, H24R, H24N, H24D, H24C, H24E, H24Q, H24G, H24I, H24L, H24M, H24P, H24T, H24W, H24Y, E27D, S29A, S29G, V30I, V30A, V30G, I33T, I33S, S35I, S35A, S35G, S35T, D37N, D37A, D37G, Y39H, Y39A, Y39G, T42A, M43I, S49Q, S49A, S49G, L51E, L51A, L51G, P52T, V53T, V53A, V53G, V54A, V54G, V54L, T55A, T55G, L59M, L59V, L59F, L59K, L59A, L59R, L59N, L59D, L59C, L59E, L59Q, L59G, L59H, L59I, L59P, L59S, L59T, L59W, L59Y, G60K, G60V, G60F, G60A, G60R, G60N, G60D, G60C, G60E, G60Q, G60II, G60I, G60L, G60M, G60P, G60S, G60T, G60W, G60Y, L61Y, L61V, L61F, L61K, L61A, L61R, L61N, L61D, L61C, L61E, L61Q, L61G, L61H, L61I, L61M, L61P, L61S, L61T, L61W, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, T84_E85T, E85_, R86N, R86_, N87L, N87_, E88_, K91Q, K91_, D92L, D92_, D92Y, H94Q, H94_, D104A, V106F, V106W, VI06Y, V106N, V106Q, V106K, V106H, V106D, V106G, V106E, DI07L, D107M, DI 07V, D107F, D107K, D107A, D107R, D107N, D107C, D107E, D107Q, D107G, D107H, D107I, D107P, D107S, D107T, D107W, D107Y, G108R, G108T, G108Q, G108L, G108K, G108W, or a combination thereof, wherein > is a deletion at that position.. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 comprises one or more substitutions selected from K20Y, H22S and II23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, and H23G wherein position 60 (Xaa60) is glycine. In1902004-0002-004-W01certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 comprises one or more substitutions selected from K20Y, H22S, __22’A and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 comprises one or more substitutions selected from K20Y, H22G,,22’A and H23S.

[0292] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 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 an ALK6 ECD sequence selected from SEQ ID NO: 132 to 155.

[0293] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 190 as shown below using standard three- letter amino acid abbreviations:

[0294] Lysi - Lys?. - Glus - Aspr Glys - Glus - Ser? - Thrs - Alas - Proio - Thn i - Proi 2. - Argi3 -Proi4 - Xaais - Xaais - Leun - Argis - Cysi9 - Xaa2o - Cys?i - Xaa22 - Xaa’22 - Xaa”22 - Xaa23 - Xaa’23 - Xaa24 - Cys25 - Pro26 - Xaa27 - Asp28 - Xaa 9 - Xaaso - Asnsi - Asn32 -Xaa33 - Cys 4 - Xaa35 - Thns - Xaa37 - Glyss - Xaa39 - Cys o - Phe4i - Xaa 2 - Xaa43 - Ile4 - Glu45 - Glu46 - Asp? - Asp s - Xaa49- Glyso - Xaasi - Xaas2 - Xaass - Xaas4 - Xaass - Serse - Glys? - Cysss - Xaas9 - Xaaso - Xaasi - Glus? - Glyss - Sers4 - Aspss - Phess - Gln67 – Cys68 -Xaa 9 - Asp?o - Xaari - Pro?2 - Xaa?3 - Xaa74 - Xaa75– Xaa76– Arg77– Arg78– Xaa79– Ile80– Glu81– Cys82– Cys83– Xaa84– Xaa85– Xaa86– Xaa87– Xaa88– Cys89– Asn90– Xaa91– Xaa92– Leu93– Xaa94– Pro95– Thr96– Leu97– Pro98– Pro99– Leu100– Lys101– Asn102– Arg103- Xaaio4 - Pheios - Vahos - Xaaio? - Xaaios - Xaaic® - Xaano - Xaam - Xaan? - Xaa113;

[0295] wherein Xaa15is K or P;

[0296] Xaa15is V or I;

[0297] Xaa20is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;

[0298] Xaa22is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S;

[0299] Xaa’22 is absent, G, S, or A;

[0300] Xaa”?.?. is absent or S;

[0301] Xaa23 is S, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G;

[0302] Xaa’23 is absent, L or H;

[0303] Xaa24is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;1902004-0002-004-W01

[0304] Xaa27 is E or D;

[0305] Xaa29 is S, G or A;

[0306] Xaa30is V, A, G or I;

[0307] Xaass is I, S or T;

[0308] Xaa35is S, T, G, A or I;

[0309] Xaa37is D, A, G or N;

[0310] Xaa39is Y, A, G or H;

[0311] Xaa42is T or A;

[0312] Xaa43 is M or I;

[0313] Xaa49is S, A, G or Q;

[0314] Xaa51is L, A, G or E;

[0315] Xaa52is P or T;

[0316] Xaa53is V, A, G or T;

[0317] Xaa54is V, A, G or L;

[0318] Xaa₅₅ is T, G or A;

[0319] Xaa59is L, M, V, F, K, A, R, N, D, C, E, Q, G, H, I, P, S, T, W, or Y;

[0320] Xaa60is G, K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T, W, or Y; Xaa61is L, Y, V, F, K, A, R, N, D, C, E, Q, G, H, I, M, P, S, T, or W;

[0321] Xaa69is R or K;

[0322] Xaa7i is T or S;

[0323] Xaa73 is I or K;

[0324] Xaa74is P or A;

[0325] Xaa75 is H or Q;

[0326] Xaa76 is Q or L;

[0327] Xaa79is S or T;1902004-0002-004-W01

[0328] Xaas4 is absent, T or R;

[0329] Xaa85 is absent, T or E;

[0330] Xaa86is absent, R or N;

[0331] Xaas? is N or L;

[0332] Xaa88 is absent, E or L;

[0333] Xaasi is absent, K or Q;

[0334] Xaa92is absent, D, Y or L;

[0335] Xaa94 is absent, H or Q;

[0336] Xaaio4 is D or A;

[0337] Xaaio7 is absent;

[0338] Xaaios is absent;

[0339] Xaaios is absent;

[0340] Xaano is absent;

[0341] Xaain is absent;

[0342] Xaaii2 is absent; and,

[0343] Xaain is absent.

[0344] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 190 comprises a substitution selected from K15P, V16I, K20Y, K20V, K20F, K20A, K20R, K20N, K20D, K20C, K20E, K20Q, K20G, K20H, K20I, K20L, K20M, K20P, K20S, K20T, K20W, H22S, H22G, H22E, H22V, H22F, H22K, H22A, H22R, H22N, H22D, H22C, H22Q, H22I, II22L, H22M, II22P, H22T, II22W, II22Y, __22’A, __22’__, 22’G. 22'S. __22?,__, __22”S, H23G, H23S, H23V, H23F, H23K, H23A, H23R, H23N, H23D, H23C, H23E, H23Q, H23I, H23L, H23M, H23P, H23T, H23W, H23Y, __23’_, _23’L, 23 ’H, H24S, H24V, H24F, H24K, H24A, H24R, H24N, H24D, H24C, H24E, H24Q, H24G, H24I, H24L, H24M, H24P, H24T, I-I24W, FI24Y, E27D, S29A, S29G, V30I, V30A, V30G, I33T, I33S, S35I, S35A, S35G, S35T, D37N, D37A, D37G, Y39H, Y39Q, Y39A, T42A, M43I, S49Q, S49A, S49G, L51E, L51A, L51G, P52T, V53T, V53A, V53G, V54A, V54G, V54L, T55A, T55G, L59M, L59V,1902004-0002-004-W01L59F, L59K, L59A, L59R, L59N, L59D, L59C, L59E, L59Q, L59G, L59H, L59I, L59P, L59S, L59T, L59W, L59Y, G60K, G60V, G60F, G60A, G60R, G60N, G60D, G60C, G60E, G60Q, G60II, G60I, G60L, G60M, G60P, G60S, G60T, G60W, G60Y, L61Y, L61V, L61F, L61K, L61A, L61R, L61N, L61D, L61C, L61E, L61Q, L61G, L61H, L61I, L61M, L61P, L61S, L61T, L61W, R69K, T71S, I73K, P74A, H75Q, Q76L, S79T, T84R, T84_E85T, E85_, R86N, R86_, N87L, N87_, E88_, K91Q, K91_, D92L, D92_, D92Y, H94Q, H94_, D104A, or a combination thereof, wherein > is a deletion at that position.. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 190 comprises one or more substitutions selected from L59M, G60K, and L61Y. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 190 comprises one or more substitutions selected from K20Y, H22S and H23G. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein comprises one or more substitutions selected from K20Y, H22S, and H23G wherein position 60 (Xaaeo) is glycine. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 190 comprises one or more substitutions selected from K20Y, H22S, _22'A and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 190 comprises one or more substitutions selected from K20Y, H22G, _22’A and H23S.

[0345] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 157 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 an ALK6 ECD sequence selected from SEQ ID NO: 158 to 189.

[0346] In embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of ALK6 according to SEQ ID NO: 437 as shown below using standard three-letter amino acid abbreviations:

[0347] Lysi - Lys2 - Glus - Asps - Glys - Glus - Ser? - Tim - Alas - Prow - Thru - Proi2 -Argis -Proi4 - Xaais - Xaais - Leui? - Argis - Cysi9 - Xaa20– Cys21– Xaa22- Xaa’22 - Xaa23 - H1S24 - Cys25 - Pro26 - Xaa27 - Asp28 - Xaa29- Xaaso - Asnsi - Asns2 - Xaass - Cysss - Xaass - Thrss - Xaa?? - Glyss - Xa s9 - Cys4o - Pl so 41 - Xaa? 2 - Xaa s - Hess - Gluss - Glu46 - Asp47 - Aspss - Xaa49 - Glyso - Xaasi - Xaas 2 - Xaass - Xaass - Xaass - Serso - Glys? - Cysss - Xaas9 - Xaaeo - Xaaei - G1U62 - Glyes - Seres - Aspes - Pheee - Glne? - Cysss - Xaa69- Asp?o - Xaa?i - Pro?? - Xaa?s - Xaa?4 - Xaass - Xaa?6 - Arg?? - Arg?s - Xa?9 - Ileso - Glusi - Cyss2 - Cysss - Xaas 4 - Xaass - Xaas6 - X as? - Xaass-Xaas9—X a9o - Xa 9i - Xaa92 - X a93 - Xa 94—Xaa9s—1902004-0002-004-W01Xaa96– Xaa97– Xaa98– Xaa99– Xaa100– Xaa101– Xaa102– Xaa103– Xaa104– Xaa105– Xaa106– Xaa107– Xaa108– Xaa109– Xaa110– Xaa111– Xaa112– Xaa113;|0348] wherein: Xaa15is K or P;

[0349] Xaa16is V or I;

[0350] Xaa2o is V, F, K orY;

[0351] Xaa22is G, H or S;

[0352] Xaa’22 is absent, G, S or A;

[0353] Xaa23is S. H or G;

[0354] Xaa27is E or D;

[0355] Xaa29 is S or A;

[0356] Xaa30is V or I;

[0357] Xaa33 is I or T;

[0358] Xaa35 is S or I;

[0359] Xaa37 is D or N;

[0360] Xaa39 is Y or H;

[0361] Xaa42is T or A;

[0362] Xaa43 is M or I;

[0363] Xaa49 is S or Q;

[0364] Xaa51 is L or E;

[0365] Xaa52is P or T;

[0366] Xaa53 is V or T;

[0367] Xaa54 is V or L;

[0368] Xaa55 is T or A;

[0369] Xaa59 is L or M;

[0370] Xaa60is G or K;1902004-0002-004-W01

[0371] Xaa61 is L or Y;

[0372] Xaa69is R or K;

[0373] Xaa71 is T or S;

[0374] Xaa73 is I or K;

[0375] Xaa74 is P or A;

[0376] Xaa75 is H or Q;

[0377] Xaa76is Q or L;

[0378] Xaa79is S or T;

[0379] Xaa84is T or R;

[0380] Xaas5 is absent, T or E;

[0381] Xaa86is R or N;

[0382] Xaas? is absent, N or L;

[0383] Xaa88 is absent, E or L;

[0384] Xaa89is absent or C;

[0385] Xaa9o is absent or N;

[0386] Xaagi is absent, K or Q;

[0387] Xaa92is absent, D or L;

[0388] Xaa93 is absent or L;

[0389] Xaa94 is absent, H or Q;

[0390] Xaa95is absent or P;

[0391] Xaa96 is absent or T;

[0392] Xaa97 is absent or L;

[0393] Xaa98is absent or P;

[0394] Xaa99 is absent or P;1902004-0002-004-W01

[0395] Xaa100 is absent, V or L;

[0396] Xaa101 is absent, V or K;

[0397] Xaa102is absent, I or N;

[0398] Xaa103 is absent, G or R;

[0399] Xaa104 is absent, P, D or A;

[0400] Xaa105 is absent or F;

[0401] Xaa106is absent, F or V;

[0402] Xaa107 is absent or D;

[0403] Xaa108 is absent or G;

[0404] Xaa109is absent, S or P;

[0405] Xaa110 is absent or I;

[0406] Xaa111is absent, R or H;

[0407] Xaa112is absent or H; and,

[0408] Xaa113is absent or R.

[0409] In embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 437 comprises a substitution selected from V16I, K20Y, H22S, _22’A, H23G, E27D, V30I, I33T, S35I, D37N, Y39H, T42A, M43I, L51M, T55A, L59M, G60K, L61Y, R68K, T71S, I73K, P74A, H75Q, Q76L, S78T or a combination thereof, wherein is a deletion at that position.

[0410] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 437 comprises one or more substitutions selected from K20Y, H22S, _22’A, and H23G. In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 437 comprises one or more substitutions selected from V16I, K20Y, H22S, 22 ’A, H23G and L51M. In certain other embodiments, the ALK6 ECD polypeptide of the fusion protein composes one or more substitutions selected from VI 61, K20Y, H22S, _22’A, II23G and L5 IM wherein position 60 (Xaaeo) is glycine.

[0411] In certain embodiments, the ALK6 ECD polypeptide of the fusion protein according to SEQ ID NO: 437 comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%,1902004-0002-004-W0186%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an ALK6 ECD sequence selected from SEQ ID NO: 90, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425 and 431.

[0412] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 3 (“SEQ ID NO: 1 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 92, 94, 96, 98, and 100.

[0413] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g,, ligand binding) of SEQ ID NO: 108 (“SEQ ID NO: 113 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified SEQ ID NO: 90, 102, 104, and 110.

[0414] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 83 (“SEQ ID NO:1 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified SEQ ID NO: 12; SEQ ID NO: 14; and SEQ ID NO: 71

[0415] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 12. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 12.

[0416] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 14. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 14.

[0417] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 71. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 71.

[0418] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 79 (“SEQ ID NO:11 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g,, ligand binding) comprises an ECD sequence of ALK6 selected from exemplified SEQ ID NOs: 15-45, 57, 59, 61, 63, 65 and 88.

[0419] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 15. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 15.

[0420] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 16. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 16.

[0421] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 17. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 17.

[0422] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 18. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 18.

[0423] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 19. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 19.

[0424] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 20. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 20.

[0425] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 21. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 21.

[0426] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 22. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 22.

[0427] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 23. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 23.

[0428] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 24. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 24.

[0429] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 25. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 25.

[0430] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 26. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 26.1902004-0002-004-W01

[0431] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 27. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 27.

[0432] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 28. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 28.

[0433] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 29. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 29.

[0434] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 30. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 30.

[0435] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 31. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 31.

[0436] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 32. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 32.

[0437] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 33. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 33.

[0438] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 34. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 34.

[0439] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 35. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 35.

[0440] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 36. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 36.

[0441] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 37. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 37.

[0442] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 38. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 38.

[0443] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 39. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 39.

[0444] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 40. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 40.

[0445] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 41. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 41.

[0446] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 42. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 42.

[0447] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 43. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 43.

[0448] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 44. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 44.

[0449] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 45. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 45.

[0450] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 57. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 57.1902004-0002-004-W01

[0451] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 59. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 59.

[0452] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 61. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 61.

[0453] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 63. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 63.

[0454] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 65. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 65.

[0455] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 88. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 88.

[0456] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 82 (“SEQ ID NO:80 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified SEQ ID NO: 67, 73, 75, and 77.

[0457] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 67. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 67.

[0458] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 73. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 73.

[0459] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 75. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 75.

[0460] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 77. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 77.

[0461] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g,, ligand binding) of SEQ ID NO: 81 (“SEQ ID NO:69 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified according to SEQ ID NO: 13, 86, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 267, 272, 277 and 283.

[0462] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 13. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 13.

[0463] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 86. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 86.

[0464] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 90. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 90.

[0465] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 92. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 92.

[0466] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 94. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 94.

[0467] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 96. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 96.

[0468] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 98. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 98.

[0469] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 100. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 100.

[0470] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 102. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 102.

[0471] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 104. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 104.

[0472] In certain embodiments, tire soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 110. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 110.

[0473] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 113. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 113.

[0474] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 157 (“SEQ ID NO:1 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified according to SEQ ID NO: 132 to 155.

[0475] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 132. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 132.

[0476] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 133. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 133.1902004-0002-004-W01

[0477] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 134. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 134.

[0478] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 135 Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 135.

[0479] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 136. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 136.

[0480] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 137. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 137.

[0481] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 138. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 138.

[0482] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 139. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 139.

[0483] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 140. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 140.

[0484] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 141. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 141.

[0485] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 142. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 142.

[0486] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 143. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 143.

[0487] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 144. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 144.

[0488] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 145. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 145.

[0489] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 146. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 146.

[0490] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 147. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 147.

[0491] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 148. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 148.

[0492] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 149. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 149.

[0493] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 150. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 150.

[0494] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 151. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 151.

[0495] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 152. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 152.

[0496] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 153. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 153.1902004-0002-004-W01

[0497] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 154. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 154.

[0498] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 155. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 155.

[0499] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 156. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 156.

[0500] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 190 (“SEQ ID NO:69 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprises an ECD sequence of ALK6 selected from exemplified according to SEQ ID NO: 158-189.

[0501] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 158. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 158.

[0502] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 159. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 159.

[0503] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 160. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 160.

[0504] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 161. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 161.

[0505] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 162. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 162.

[0506] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 163. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 163.

[0507] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 164. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 164.

[0508] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 165. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 165.

[0509] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 166. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 166.

[0510] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 167. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 167.

[0511] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 168. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 168.

[0512] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 169. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 169.

[0513] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 170. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 170.

[0514] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 171. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 171.

[0515] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 172. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 172.

[0516] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 173. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 173.1902004-0002-004-W01

[0517] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 174. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 174.

[0518] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 175. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 175.

[0519] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 176. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 176.

[0520] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 177. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 177.

[0521] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 178. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 178.

[0522] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 179. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 179.

[0523] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 180. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 180.

[0524] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 181. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 181.

[0525] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 182. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 182.

[0526] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 183. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 183.

[0527] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 184. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 184.

[0528] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 185. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 185.

[0529] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 186. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 186.

[0530] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 187. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 187.

[0531] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 188. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 188.

[0532] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 189. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 189.

[0533] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 191. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 191.

[0534] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 192. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 192.

[0535] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 193. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 193.

[0536] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 194. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 194.

[0537] 1902004-0002-004-W01

[0538] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 202. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 202.

[0539] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 213. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 213.

[0540] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 218. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 218.

[0541] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 223. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 223.

[0542] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 228. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 228.

[0543] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 233. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 233.

[0544] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 242. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 242.

[0545] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 247. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 247.

[0546] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 252. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 252.

[0547] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 257. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 257.

[0548] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 262. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 262.

[0549] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 267. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 267.

[0550] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 272. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 272.

[0551] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 277. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 277.

[0552] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 283. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 283.

[0553] In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) of SEQ ID NO: 437 (“SEQ ID NO:90 variants”). In certain embodiments, the soluble ALK-6 polypeptide comprises an active portion (e.g., ligand binding) comprising an ECD sequence of ALK6 selected from exemplified sequences according to SEQ ID NO: 286, 292, 298, 304, 310, 316, 322, 328, 334, 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425 and 431.

[0554] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 286. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 286.

[0555] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 292. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 292.

[0556] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 298. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 298.

[0557] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 304. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 304.1902004-0002-004-W01

[0558] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 310. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 310.

[0559] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 316. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 316.

[0560] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 322. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 322.

[0561] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 328. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 328.

[0562] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 334. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 334.

[0563] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 340. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 340.

[0564] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 346. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least 70%,1902004-0002-004-W0175%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 346.

[0565] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 352. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 352.

[0566] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 358. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 358.

[0567] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 364. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 364.

[0568] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 370. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 370.

[0569] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 376. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 376.

[0570] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 382. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 382.

[0571] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 388. Therefore ALK6 polypeptides may, for example,1902004-0002-004-W01comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 388.

[0572] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 394. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 394.

[0573] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 400. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 400.

[0574] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 406. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 406.

[0575] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 412. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 412.

[0576] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 418. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 418.

[0577] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 425. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 425.1902004-0002-004-W01

[0578] In certain embodiments, the soluble ALK6 polypeptide comprises an ECD sequence of ALK6 according to SEQ ID NO: 431. Therefore ALK6 polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 431.

[0579] In certain embodiments, the ALK6 ECD polypeptide portion of the soluble ALK6 fusion protein (“BMP antagonist fusion protein”) is selected from the group consisting of: SEQ ID NOs: 1, 3-5, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79-83, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 108, 109, 110, 113, 132-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, 431 and 437. For example, the ALK6 ECD polypeptide portion of the BMP antagonist fusion protein may comprise an amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1, 3-5, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79-83, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 108, 109, 110, 113, 132-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, 431 and 437.

[0580] In certain embodiments, ALK6 ECD polypeptide portion of the soluble ALK6 fusion protein (“BMP antagonist fusion protein”) is selected from the group consisting of: SEQ ID NO: 33, 86, 88, 90, 233, 242, 283 and 286. For example, the ALK6 ECD polypeptide portion of the BMP antagonist fusion protein may comprise an amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 33, 86, 88, 90, 233, 242,283 and 286.

[0581] In embodiments, the ALK6 ECD polypeptide can be adjoined to a heterologous domain sequence which aid formation and stability of homodimer soluble ALK6 polypeptides. In certain embodiments, the heterologous domain can be derived from the constant region of an antibody (i.e., the Fc region or the hinge region between the CHI and CH2 domains). In certain embodiments, the Fc region of the fusion protein is exemplified as:THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG1902004-0002-004-W01KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 10).

[0582] In certain embodiments, the Fc region of the fusion protein is exemplified as:THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 106)

[0583] In certain embodiments, the Fc region of the fusion protein is exemplified as:THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 107)

[0584] In certain embodiments, the Fc region of the fusion protein is exemplified as:THTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 285)

[0585] In certain embodiments, the heterologous domain of the fusion protein comprises the cysteine core of the amino acid sequence from the hinge region of IgGl, IgG2, IgG3 or IgG4, For example, EPKSCDKTHTCPPCPAPELLGGP (SEQ ID NO: 196); ERKCCVECPPCPAPPVAGP (SEQ ID NO: 197); ESKYGPPCPSCPAPEFLGGP (SEQ ID NO: 198); THTCPPCPAPEAAGGP (SEQ ID NO: 199); THTCPPCKCPEAAGGP (SEQ ID NO: 200); and PTIKPCPPCKCPAP (SEQ ID NO: 201).

[0586] Other heterologous domain sequences may also be suitable as would be understood by those of ordinary skill in the art. It is also understood that for certain animal studies murine or the like, homologous Fc sequences are used as needed to test the ALK6 ECD polypeptides of this disclosure.1902004-0002-004-W01

[0587] In embodiments, the ALK6 ECD polypeptide can be adjoined to a heterologous domain sequence as a fusion protein using a linker peptide. In certain embodiments, the linker peptide can be selected from the group consisting of:TGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 6);TGGG (SEQ ID NO: 7); and,EAAAKEAAAKEAAAKEAAAK (SEQ ID NO: 8).

[0588] Other linker peptides may also be suitable as would be understood by those of ordinary skill in the art. See for example SEQ ID NO: 84 and 85

[0589] In embodiments, the fusion protein can include a leader peptide. In certain embodiments, the leader peptide can be MGWSCIILFLVATATGVHS (SEQ ID NO: 9). Other leader peptides may also be suitable as would be understood by those of ordinary skill in the art. One of skill in the art also understands the leader sequence is cleaved as part of processing resulting in a mature processed polypeptide sequence (e.g. SEQ ID NO: 1). Accordingly, the ALK6-Fc fusion proteins of this disclosure used for the treatment of a human disease do not include a leader sequence,

[0590] Provided herein are a number of exemplified soluble ALK6 fusion polypeptides (proteins) comprising an ALK6 ECD sequence portion, a linker sequence portion and an Fc sequence portion according to any of the portion sequences (e.g., ALK6 ECD, linker and FC) described above and herein. In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence selected from SEQ ID NO: 46-50, 52-56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 84, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 111, 112, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 203, 214, 219, 224, 229, 234, 238, 243, 248, 253, 258, 263, 268, 273, 278, 282, 284, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432.

[0591] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 46, Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 46.

[0592] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 47. Therefore ALK6 fusion polypeptides may, for1902004-0002-004-W01example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 47.

[0593] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 48. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 48.

[0594] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 49, Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 49.

[0595] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 50. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 50.

[0596] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 52. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 52.

[0597] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 53. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 53,

[0598] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 54. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 54.

[0599] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 55. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 55.

[0600] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 56. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 56.

[0601] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 60. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 60.

[0602] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 62. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 62.

[0603] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 64. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 64.

[0604] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 66. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 66.

[0605] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 68. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 68.

[0606] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 70. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 70.

[0607] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 72. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 72.

[0608] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 74. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 74.

[0609] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 76. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 76.

[0610] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 78. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 78.

[0611] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 84. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 84.

[0612] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 85. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 85.

[0613] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 87. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 87.

[0614] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 89. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 89.

[0615] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 91. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 91.

[0616] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 93. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 93.

[0617] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 95. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 95.

[0618] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 97. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 97.

[0619] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 99. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 99.

[0620] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 101. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 101.

[0621] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 103. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 103.

[0622] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 105. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 105.

[0623] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 111. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 111.

[0624] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 112. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 112.

[0625] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 114. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 114.

[0626] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 115. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 115.

[0627] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 116. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 116.

[0628] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 117. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 117.

[0629] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 118. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 118.

[0630] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 119. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 119.

[0631] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 120. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 120.

[0632] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 121. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 121.

[0633] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 122. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 122.

[0634] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 123. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 123.

[0635] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 124. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 124.

[0636] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 125. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 125.

[0637] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 126. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 126.

[0638] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 127. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 127.

[0639] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 128. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 128.

[0640] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 129. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 129.

[0641] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 203. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 203.

[0642] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 204. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 204.

[0643] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 205 Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 205.

[0644] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 206. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 206.

[0645] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 207. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 207.

[0646] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 208. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 208.

[0647] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 209. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 209.

[0648] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 210. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 210.

[0649] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 211. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 211.

[0650] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 212. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 212.

[0651] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 214. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 214.

[0652] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 215. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 215.

[0653] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 216. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 216.

[0654] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 217. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 217.

[0655] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 219. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 219.

[0656] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 220. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 220.

[0657] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 221. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 221.

[0658] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 222. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 222.

[0659] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 224. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 224.

[0660] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 225. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 225.

[0661] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 226. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 226.

[0662] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 227. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 227.

[0663] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 229. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 229.

[0664] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 230. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 230.

[0665] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 231. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 231.

[0666] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 232. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 232.

[0667] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 234. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 234.

[0668] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 235. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 235.

[0669] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 236. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 236.

[0670] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 237. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 237.

[0671] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 238. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 238.

[0672] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 239. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 239.

[0673] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 240. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 240.

[0674] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 241. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 241.

[0675] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 243. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 243.

[0676] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 244. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 244.

[0677] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 245. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 245.

[0678] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 246. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 246.

[0679] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 248. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 248.

[0680] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 249. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 249.

[0681] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 250. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 250.

[0682] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 251. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 251.

[0683] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 253. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 253.

[0684] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 254. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 254.

[0685] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 255. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 255.

[0686] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 256. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 256.

[0687] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 258. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 258.

[0688] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 259. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 259.

[0689] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 260. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 260.

[0690] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 261. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 261.

[0691] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 263. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 263.

[0692] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 264. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 264.

[0693] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 265. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 265.

[0694] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 266. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 266.

[0695] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 268. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 268.

[0696] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 269. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 269.

[0697] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 270. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 270.

[0698] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 271. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 271.

[0699] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 273. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 273.

[0700] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 274. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 274.

[0701] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 275. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 275.

[0702] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 276. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 276.

[0703] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 278. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 278.

[0704] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 279. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 279.

[0705] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 280. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 280.

[0706] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 281. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 281.

[0707] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 282. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 282.

[0708] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 283. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 283.

[0709] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 284. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 284.

[0710] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 287. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 287.

[0711] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 293. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 293.

[0712] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 299. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 299.

[0713] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 305. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 305.

[0714] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 311. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 311.

[0715] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 317. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 317.

[0716] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 323. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 323.

[0717] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 329. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 329.

[0718] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 335. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 335.

[0719] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 341. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 341.

[0720] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 347. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 347.

[0721] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 353. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 353.

[0722] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 359. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 359.

[0723] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 365. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 365.

[0724] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 371. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 371.

[0725] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 377. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 377.

[0726] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 383. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 383.

[0727] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 389. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 389.

[0728] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 395 Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 395.

[0729] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 401. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 401.

[0730] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 413. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of an amino acid sequence that is at least1902004-0002-004-W0170%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to ALK6 of SEQ ID NO: 413.

[0731] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 419. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 419.

[0732] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 426. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 426.

[0733] In certain embodiments, the soluble ALK6 fusion polypeptide comprises an amino acid sequence according to SEQ ID NO: 432. Therefore ALK6 fusion polypeptides may, for example, comprise, consists essentially of, or consists of 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 ALK6 of SEQ ID NO: 432.

[0734] In certain embodiments, the soluble ALK6 fusion polypeptides (not including the leader peptide (e.g., SEQ ID NO: 9)) can be selected from the group consisting of: SEQ ID NOs: 46-50, 52-56, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 84, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 111, 112, 114-129, 203, 214, 219, 224, 229, 234, 238, 243, 248, 253, 258, 63, 268, 73, 278, 282, 284, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432. For example, the ALK6 fusion polypeptides may comprise an amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of:: SEQ ID NOs: 46-50, 52-56, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 84, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 111, 112, 114-129, 203, 214, 219, 224, 229, 234, 238, 243, 248, 253, 58, 263, 268, 273, 278, 282, 284, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432.

[0735] In certain embodiments, soluble ALK6 fusion polypeptides (not including the leader peptide (e.g., SEQ ID NO: 9)) can be selected from the group consisting of: SEQ ID NOs: 87, 89, 91, 112, 234, 243, 284 and 287. For example, the ALK6 fusion polypeptides may1902004-0002-004-W01comprise an amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of:: SEQ ID NOs: 87, 89, 91, 112, 234, 243, 284 and 287.

[0736] Other fusion proteins may also be derived from this disclosure as would be understood by those of ordinary skill in the art.

[0737] Compositions and Pharmaceutical Formulations

[0738] The polypeptides described herein may be combined with one or more pharmaceutically acceptable carriers prior to administration to a host. A pharmaceutically acceptable carrier is a material that is not biologically or otherwise undesirable, e.g., the material may be administered to a subject, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Suitable pharmaceutical carriers and their formulations are described in, for example, Remington ’s: The Science and Practice of Pharmacy’, 21stEdition, David B. Troy, ed,, Lippicot Williams & Wilkins (2005), Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carriers include, but are not limited to, sterile water, saline, buffered solutions like Ringer's solution, and dextrose solution. The pH of the solution is generally from about 5 to about 8 or from about 7 to about 7.5. Other carriers include sustained-release preparations such as semipermeable matrices of solid hydrophobic polymers containing polypeptides or fragments thereof. Matrices may be in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. Carriers are those suitable for administration of polypeptides and / or fragments thereof to humans or other subjects. Pharmaceutical compositions may also include carriers, thickeners, diluents, buffers, preservatives, surface active agents, adjuvants, immunostimulants, in addition to the immunogenic polypeptide. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents and anesthetics. The pharmaceutical composition may be administered orally, parentally, by inhalation spray, rectally, intranodally, or topically in dosage unit formulations containing1902004-0002-004-W01conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term “■pharmaceutically acceptable carrier” or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a nucleic acid, polypeptide, or peptide as a pharmaceutical composition. A “pharmaceutical composition” is a composition comprising a therapeutically effective amount of polypeptide and / or fusion protein disclosed herein.

[0739] Methods for treating one or more disease conditions in a mammalian host comprising administering to the mammal at least one or more effective doses of one or more binding agents (and / or derivative(s) thereof) described herein are also provided, as disclosed in more detail below. In some embodiments, one or more polypeptides and / or fusion proteins and / or compositions comprising the same may be administered in a dosage amount of about 1 to about 50 mg (of polypeptide or protein) / kg, about 1 to about 30 mg / kg, or about 5 to about 30 mg / kg (e.g., about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, or 40 mg / kg). In certain embodiments, the one or more polypeptides and / or fusion proteins and / or compositions comprising the same may be administered to the mammal (e.g., intradermally, intravenously, orally, rectally) at about 10 mg / kg one or more times. When multiple doses are administered, the doses may comprise about the same or different amount of binding agent in each dose. The doses may also be separated in time from one another by the same or different intervals. For instance, the doses may be separated by about any of 6, 12, 24, 36, 48, 60, 72, 84, or 96 hours, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, 12 months, 1.5 years, 2 years, 3 years, 4 years, 5 years, or any time period before, after, and / or between any of these time periods. In some embodiments, the polypeptides and / or fusion proteins and / or compositions comprising the same may be administered in conjunction with other agents (e.g., anti-infective agents and / or chemotherapeutic agent). Such other agents may be administered about simultaneously with the polypeptides and / or fusion proteins and / or compositions comprising the same, or at a different time and / or frequency. Other embodiments of such methods may also be appropriate as could be readily determined by one of ordinary skill in the art.

[0740] Methods of Treatment1902004-0002-004-W01

[0741] The present disclosure relates to methods for the treatment of a vascular inflammation. Provided herein is a method for the treatment of vascular inflammation in a human subject in need thereof (alleviating one or more symptoms, or stasis of one or more symptoms) by¬ administering to the human subject a therapeutically effective amount of a composition provided herein. Hie treatment can result in improving the patient's condition and can be assess by determining if one or more of the following factors has occurred: decreased macular edema, or increased visual acuity. Tire compounds described herein can also be used in medicaments for the treatment of diabetic retinopathy.

[0742] As used herein “patient” and “human subject in need thereof’ are used interchangeably. As used herein, “patient” or “human subject in need thereof ’ is a human who exhibits one or more clinical manifestations and / or symptoms of a disease or disorder described herein. In certain situations, the patient may be asymptomatic and yet still have clinical manifestations of the disease or disorder. In one embodiment, a patient to be treated is a human being. The patient may be an individual who has been diagnosed as suffering from a condition associated with vascular inflammation or who is suspected of, or at risk of, suffering from a condition vascular inflammation, in particular vascular inflammation affecting the coronaryvessels.

[0743] Endothelial dysfunction (usually determined clinically as an endothelium-dependent vasomotor disorder (eg, an imbalance between vasodilation and vasoconstriction)) is an endothelial cell (a cell that aligns with the inner surface of blood vessels, arteries and veins) ) Physiological inability, and the cells impede their normal biochemical functions. Normal endothelial cells are necessary for the control of coagulation, platelet adhesion, immune function, volume and electrolyte content of gaps inside and outside the blood vessels. Endothelial dysfunction is closely associated with pro-inflammatory, pro-oxidative and prothrombotic changes within the arterial wall. Endothelial dysfunction is considered an important event in the development and progression of atherosclerosis and arteriosclerosis and precedes clinically distinct vascular complications. The prognosis of endothelial dysfunction is important for the detection of vascular diseases and the prediction of adverse vascular events. Risk factors for atherosclerosis and vascular disease / event are closely related to endothelial dysfunction. Endothelial damage also contributes to kidneydamage and / or chronic or progressive kidney damage, such as ductal fibrosis, glomerulonephritis, microalbumin or macroalbuminuria, nephropathy and / or chronic kidney disease or renal failure.1902004-0002-004-W01

[0744] In embodiments, vascular inflammation disorder is selected from atherosclerosis, kidney failure, liver steatosis, obesity, diabetes, restenosis, lung fibrosis, pulmonary arterial hypertension (PAH) right sided heart failure and pulmonary hypertension (PH) righ t sided heart failure. In certain embodiments, vascular inflammation disorders are selected from pulmonary hypertension (PH), pulmonary arterial hypertension right sided heart failure, pulmonary' arterial hypertension (PAH), cardiovascular disease, cardiac calcification, atrial fibrillation, diabetic or primary' cardiomyopathy (DCM), myocardial hypertrophy, cardiac hypertrophy, myocardial fibrosis, vasculitis, Giant cell arteritis, Granulomatosis with polyangiitis (GPA), Buerger's disease, IgA vasculitis, Kawasaki disease, Takayasu arteritis, Fibromuscular dysplasia (FMD), Primary lymphedema, Secondary lymphedema, diabetic ulcers, and diabetic nephropathy.

[0745] In certain embodiments, the vascular inflammation disorder is a peripheral artery disease selected from Intestinal ischemic syndrome, Renal artery disease, Popliteal Entrapment Syndrome, Raynaud's Phenomenon, Buerger's Disease and lymphedema. In certain embodiments, the vascular inflammation disorder is diabetic cardiomyopathy (DCM) or diabetic nephropathy.

[0746] In embodiments, the vascular inflammation disease or condition is selected from pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, cardiac valvular malformations, cardiac structural malformations, fibrodysplasia ossificans progressiva, juvenile familial polyposis syndrome, parathyroid disease, anemia, vascular calcification, atherosclerosis, valve calcification, renal osteodystrophy, ankylosing spondylitis, vascular inflammation, anemia of inflammation, inflammatory bowel disease, seronegative spondyloarthropathies, psoriasis, and atherosclerosis.

[0747] In another aspect, the invention provides a method of reducing primary and secondary cardiovascular events arising from coronary, cerebral, or peripheral vascular disease in a subject, comprising administering an effective amount of a compound as disclosed herein.

[0748] In another aspect, the invention provides a method of preventing cardiovascular disease in a subject with elevated markers of cardiovascular risk, comprising administering an effective amount of a compound as disclosed herein.

[0749] Atherosclerosis is a chronic arterial wall disease that is characterized by chronic inflammation and the accumulation of atheromatous lesions in the inner layer of arteries. BMPs have been implicated in atherosclerosis progression by regulating endothelial inflammation and cell differentiation. BMP-2 and -4 have been shown to induce proinflammatory effects in the ECs. Besides, inhibiting BMP signaling pathway by MGP resulted in reduced atherosclerotic1902004-0002-004-W01lesions formation in apolipoprotein (Apo) E knockout mice, while enhanced BMP activity led to increased atherosclerotic lesions formation in Apo E knockout mice.

[0750] Atherosclerosis is the most common cause of aortic aneurysms, a vascular disease. It has been shown that in 2 -week post thoracic aortic aneurysms induction mice, the expression level of BMP signal components and BMP regulators were elevated in mRNA level, indicating that activation of BMP signaling may also be involved in the pathogenesis of aortic aneurysms.

[0751] One key histological and clinical event of atherosclerosis is vascular calcification, which is known as the abnormal deposition of calcium phosphate salts in blood vessels, myocardium, and cardiac valves. Vascular calcification is a tightly regulated process which leads to differentiation of cells such as SMCs or pericytes into osteoblast-like cells, and the mineralization of the extracellular matrix. It is speculated that the course of vascular calcification shares many similarities with that of bone mineralization. Pericytes, mesenchymal stem cells, multipotent cells from the adventitia, resident cells in the media or intima and transdifferentiated SMCs, are the possible cells which transdifferentiate into osteoblast-like cells in blood vessels. It has been suggested that vascular endothelial cells may contribute to osteogenic differentiation; ECs can transdifferentiate into mesenchymal stem cells through a process termed endothelial to mesenchymal transition (EndoMT).

[0752] Interestingly, in fibrodysplasia ossificans progressiva (FOP), a disease characterized by overactive osteoblasts and ectopic bone formation and linked to a point mutation in BMP type I receptor ALK2, it was shown that ECs can acquire a progenitor-like phenotype and differentiate into bone forming osteoblastic cells.

[0753] BMPs expression is increased at vascular calcification sites; in addition BMPs can trigger the differentiation of multipotential cells into the osteogenic lineage.

[0754] This raises the possibility that BMPs may be involved in the process of vascular calcification. Indeed it was shown that BMPs can direct osteogenic programming of vascular mesenchymal progenitors of the pericyte lineage and that they can promote expression of osteoblast lineage markers such as alkaline phosphatase in cultured vascular SMCs. It has been shown that BMP-2 and the osteoblast homeoprotein Msx2 were expressed during the osteogenic process in the aorta of diabetic patients. The BMP-2-Msx2 signaling pathway may enhance vascular calcification by promoting the differentiation of myofibroblasts into the osteogenic lineage. In addition BMP-2 enhances the expression of Runx2, a core transcription factor that is known to regulate osteoblast and chondrocyte differentiation and promote vascular SMCs calcification by increasing oxidative stress and endoplasmic reticulum (ER) stress in human coronary artery SMCs. Interestingly, the inhibition of oxidant stress or ER1902004-0002-004-W01stress reversed this gene expression pattern and mineralization process. Moreover, recent research showed that BMPs are involved in vascular calcification in low-density lipoprotein (LDL) receptor-deficient (LDLR− / −) mice.

[0755] The present invention further relates to metabolic diseases (e.g., diabetes, in particular type 2 diabetes mellitus) and / or diseases associated therewith, diabetic complications in microvascular or large blood vessels, e.g,, diabetic retinopathy, diabetic neuropathy, diabetes mellitus. Provided herein are ALK-6 polypeptides of this disclosure to treat and / or prevent in patients with or at risk for diabetic nephropathy or cardiovascular or cerebrovascular disease (e.g., myocardial infarction, stroke or peripheral arterial occlusive disease).

[0756] Type 2 diabetes mellitus is a complex condition that is centrally involved in the dual endocrine action of insulin resistance and impaired insulin secretion, which does not meet the requirements necessary to maintain plasma glucose levels within the normal range. It is a common chronic and progressive disease that arises from physiology. This results in hyperglycemia and its associated microvascular and macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (e.g., cardiovascular or cerebrovascular) complications. The elements of vascular disease play an important role. Frequent complications result in a significant shortening of life expectancy. At present, diabetes is the leading cause of adult onset blindness, renal failure, and leg amputation in an industrialized society due to diabetes-induced complications, with a 2- to 5-fold increase in cardiovascular death risk.

[0757] In another aspect, the invention provides a method of preventing and treating hepatic dysfunction in a subject associated with nonalcoholic fatty liver disease (NAFLD), steatosis- induced liver injury’, fibrosis, cirrhosis, or non-alcoholic steatohepatitis (NASH) in a subject comprising administering an effective amount of a compound as disclosed herein.

[0758] Atherosclerosis

[0759] Atherosclerosis is a progressive process in which an artery wall thickens as a result of invasion and accumulation of white blood cells. This inflammatory process results in plaques within the vessel wall containing living white blood cells, dead cell debris and fatty deposits including cholesterol and triglycerides.

[0760] Stable atherosclerotic plaques, which tend to be asymptomatic, are typically rich in extracellular matrix and smooth muscle cells, while unstable plaques are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap1902004-0002-004-W01eventually induce clot formation in the lumen, and such clots can block arteries or detach, move into the circulation and eventually block smaller downstream vessels causing thromboembolism. Chronically expanding plaques are frequently asymptomatic until vessel occlusion (stenosis) is severe enough that blood supply to downstream tissue is insufficient.

[0761] Atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations and blood flow is not immediately affected. Indeed, plaque ruptures are also asymptomatic unless they result in sufficient narrowing or closure of an artery / that impedes blood flow to different organs so as to induce symptoms. Typically, the disease is only diagnosed when the patient experiences other cardiovascular disorders such as stroke or heart attack. Symptomatic atherosclerosis is typically associated with men in their 40s and women in their 50s to 60s. Sub-clinically, the disease begins to appear in childhood, and noticeable signs can begin developing at puberty. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes,

[0762] Atherosclerosis may cause narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, and this can produce symptoms such as tire chest pain of angina, shortness of breath, sweating, nausea, dizziness or light-headedness, breathlessness or palpitations. Cardiac arrhythmias may also result from cardiac ischemia. Atherosclerosis that causes narrowing in the carotid arteries, which supply blood to the brain and neck, can produce symptoms such as a feeling of weakness, not being able to think straight, difficulty’ speaking, becoming dizzy and difficulty in walking or standing up straight, blurred vision, numbness of the face, arms, and legs, severe headache and losing consciousness. These symptoms may also be present in stroke, which is caused by marked narrowing or closure of arteries going to the brain leading to brain ischemia and death of cells in the brain. Peripheral arteries, which supply blood to the legs, arms, and pelvis may also be affected. Symptoms can include numbness within the affected limbs, as well as pain. Plaque formation may also occur in the renal arteries, which supply blood to the kidneys. Plaque occurrence and accumulation leads to decreased kidney blood flow and chronic kidney disease, which, like all other areas, are typically asymptomatic until late stages.

[0763] Vascular inflammation is a key feature in atherogenesis and plays a critical role in atherosclerotic plaque stability by triggering plaque rupture leading to acute coronary syndromes (see Ross R. N Engl J Med 1999; 340:115-26, and Major A S et al Circulation 2011; 124:2809-11). Importantly, more than 50% of acute coronary syndromes are caused by highly inflamed but anatomically non-significant atherosclerotic plaques (Fishbein M C et al.1902004-0002-004-W01Circulation 1996; 94:2662-6), which are not identifiable by any of the existing clinical diagnostic tests.

[0764] Perivascular adipose tissue (PVAT) surrounds (coronary) arteries and may be involved in local stimulation of atherosclerotic plaque formation. PVAT can be quantified using a number of techniques, including for example, echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI). The quantity of PVAT correlates with some parameters of metabolic syndrome including increased waist circumference, hypertriglyceridemia and hyperglycemia, and with coronary atherosclerosis. PVAT has long been known to secrete pro-inflammatory proteins and induce inflammation of the artery wall. Tire long-held understanding of the pathology of atherogenesis in the vascular wall was that it is stimulated externally, and it was suggested that PVAT played a key role in this process.

[0765] It has recently become clear that vascular inflammation and oxidative stress has the ability to affect the biology of PVAT as the vascular wall releases mediators able to exert a paracrine effect on the neighboring PVAT (see e.g. Margaritis et al. Circulation 2013; 127(22):2209-21). This observation was in contrast to the classical theory according to which PVAT sends paracrine signals to the vascular wall. It is now understood that the biology of PVAT is shaped by signals received from the blood vessel it surrounds, and characterization of PVAT can provide useful information regarding the biology and health of that blood vessel.

[0766] Treatment of Atherosclerosis

[0767] Abundant evidence suggests that BMP ligands are pro-inflammatory and pro-atherogenic in the blood vessel wall (Chang et al. Circulation 116:1258-1266, 2007). Knocking-down expression of BMP4 decreased inflammatory signals, whereas knockingdown BMP inhibitors (eg follistatin or noggin) increased inflammatory signals. Compounds as described herein can be used to reduce vascular inflammation associated with atherosclerosis, and other vasculitis. By decreasing atherosclerosis, it would be anticipated that compounds as described herein would decrease the incidence and / or severity of acute coronary syndromes (angina pectoris and heart attack), transient ischemic attacks, stroke, peripheral vascular disease, and other vascular ischemic events. Moreover, in so far as atherosclerosis contributes to the pathogenesis of aneurysm formation, compounds as described herein can be used to slow the progression of aneurysm formation decreasing the frequency of aneurismal rupture and the requirement for surgery.

[0768] As BMPs and many of the BMP -induced gene products that affect matrix remodeling are overexpressed in early atherosclerotic lesions, BMP signals may promote atherosclerotic plaque formation and progression (Bostrom et al. J Clin Invest. 91: 1800-1809. 1993; Dhore et1902004-0002-004-W01al. Arterioscler Thromb Vase Biol. 21: 1998-2003. 2001). BMP signaling activity in the atheromatous plaque may thus represent a form of maladaptive injury -repair, or may contribute to inflammation. Over time, BMP signals may also induce resident or nascent vascular cell populations to differentiate into osteoblast-like cells, leading to intimal and medial calcification of vessels (Hruska et al. Circ Res. 97: 105-112. 2005). Calcific vascular disease, or arteriosclerosis, is associated with decreased vascular distensibility, and increased risk of cardiovascular events and mortality, and is particularly problematic when associated with underlying atherosclerotic disease (Bostrom et al. Crit Rev Eukaryot Gene Expr. 10: 151-158.2000). Both atherosclerotic and calcific lesions may be amenable to regression, however, if signals which contribute to their progression can be intercepted (Sano et al. Circulation. 103: 2955-2960. 2001). In certain aspects, inhibitor of BMP type I receptor activity may be used to limit the progression of atheromatous plaques and vascular calcification in vivo (Derwall et al. Arteriosclerosis, Thrombosis, and Vascular Biology, 2012; 32: 613-622),

[0769] Treatment of Systemic Hypertension

[0770] Infusion of BMP4 induces systemic hypertension in mice (Miriyala et al. Circulation 113:2818-2825, 2006). Vascular smooth muscle cells express a variety of BMP ligands. BMPs increase the expression of voltage gated potassium channels and thereby increase constriction of vascular smooth muscle (Fantozzi et al. Am. J. Physiol. Lung Cell. Mol. Physiol. 291: L993-1004, 2006). Compounds as described herein that inhibit BMP signaling can be used to reduce blood pressure. Sustained reduction of blood pressure in patients with hypertension would be expected to prevent myocardial infarction, congestive heart failure, cerebrovascular accidents, and renal failure. BMP inhibitors as described herein can be used to target the hypertension in specific vascular beds, such as in pulmonary hypertension via local delivery’ (e.g., via aerosol).

[0771] Treatment of Pulmonary Hypertension

[0772] BMP signaling contributes to t...

Claims

1. 1902004-0002-004-W01CLAIMSWe claim:

1. A method for treatment of vascular inflammation in a human subject in need thereof comprising: administering an effective amount of a pharmaceutical composition to the subject, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 108; SEQ ID NO: 109; SEQ ID NO: 130, SEQ ID NO: 157, SEQ ID NO: 190 and SEQ ID NO: 437.

2. A method for treatment of vascular inflammation in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88?% 89%, 90%, 91?% 92%, 93%, 94?% 95%, 96%, 97?% 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425, or 431.

3. The method of claim 1 or 2, wherein the ALK6 ECD sequence comprises at least one point mutation as compared to SEQ ID NO: 1.

4. The method of any preceding claim, wherein the soluble recombinant bone morphogenetic protein receptor type- IB fusion protein 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 SEQ ID NO: 86, SEQ ID NO: 88 or SEQ ID NO: 90.1902004-0002-004-W015. A method for treatment of vascular inflammation in a human subject in need thereof, comprising:administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 3, 5, 79, 81, 82, 83, 108, 109, 112, 130, 157 or 190.

6. The method of any preceding claim, wherein the ALK6 ECD 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 SEQ ID NO: 69.

7. The method of any preceding claim, wherein the ALK6 ECD 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 SEQ ID NO: 90.

8. The method of any preceding claim, wherein the ALK6 ECD 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 SEQ ID NO: 286.

9. I'he method of any preceding claim, wherein the ALK6 ECD 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 SEQ ID NO: 233 or SEQ ID NO:242.

10. The method of any preceding claim, wherein the point mutation is selected from one or more ofV16I; K20Y, K20F, FI22S, _22’A, II23G, V30I, I33T, I33S, S35I, S49Q and L51M.

11. I'he method of any preceding claim, wherein the heterologous sequence is an Fc sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

12. Tire method of claim 1, 2 or 3, wherein the heterologous sequence is an Fc sequence according to SEQ ID NO: 106.1902004-0002-004-W0113. The method of claim 1, wherein the fusion protein binds one or more of BMP2, BMP4, BMP6, BMP7, GDF5, GDF6, GDF7 and / or BMP 10.

14. Tire method of any preceding claim, wherein the polypeptide binds BMP10.

15. Tire method of any preceding claim, wherein the polypeptide does not bind BMP 10.

16. The method of claim 1, wherein the ALK6 ECD sequence is selected from SEQ ID NO: 190 and the sequence comprises point mutations K20Y and H22S,17. The method of claim 1, wherein the ALK6 ECD sequence is selected from SEQ ID NO: 190 and tire sequence comprises point mutations K20Y, H22S and I33T.

18. Ihe method of claim 1, wherein the ALK6 ECD sequence is selected from SEQ ID NO: 190 and the sequence comprises point mutations H22S and I33T.

19. Tire method of any preceding claim, wherein the heterologous region is an Fc region.

20. The method of any preceding claim, wherein the vascular inflammation disorder is selected from atherosclerosis, kidney failure, liver steatosis, obesity, diabetes, restenosis, lung fibrosis, pulmonary arterial hypertension (PAH) right sided heart failure and pulmonary hypertension (PH) right sided heart failure.

21. Ihe method of any preceding claim, wherein the vascular inflammation disorder is selected from pulmonary hypertension (PH), pulmonary arterial hypertension right sided heart failure, pulmonary arterial hypertension (PAH), cardiovascular disease, cardiac calcification, atrial fibrillation, diabetic or primary cardiomyopathy (DCM), myocardial hypertrophy, cardiac hypertrophy, myocardial fibrosis, vasculitis, Giant cell arteritis, Granulomatosis with polyangiitis (GPA), Buerger's disease, IgA vasculitis, Kawasaki disease, Takayasu arteritis, Fibromuscular dysplasia (FMD), Primary lymphedema, Secondary lymphedema, diabetic ulcers, and diabetic nephropathy.

22. Tire method of claim 1, wherein the vascular inflammation disorder is a peripheral artery disease.

23. The method of claim 18, wherein the peripheral artery disease is selected from Intestinal ischemic syndrome, Renal artery disease, Popliteal Entrapment Syndrome, Raynaud's Phenomenon, Buerger's Disease and lymphedema.

24. Ihe method of claim 1, wherein the vascular inflammation disorder is diabetic cardiomyopathy (DCM) or diabetic nephropathy.

25. Tire method of claim 1, wherein treating comprises reducing microvascular endothelial dysfunction, reducing metabolic inflammation, reducing hyperglycemia and / or reducing immune inflammation.1902004-0002-004-W0126. The method of claim 1, wherein the ALK-6 Fc fusion polypeptide is administered as monotherapy for the vascular inflammation disorder.

27. Tire method of claim 1, wherein the ALK-6 Fc fusion polypeptide is administered as adjunct therapy with an additional treatment for the vascular inflammation disorder.

28. A method for treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID NO: 91, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432.

29. The method of claim 28, wherein the fusion protein compri ses 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 SEQ ID NO: 91.

30. The method of claim 28, wherein the fusion protein 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 SEQ ID NO: 287.

31. A method for treatment of pulmonary arterial hypertension (PAH) in a human subject in need thereof comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 ECD polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 108; SEQ ID NO: 109; SEQ ID NO: 130, SEQ ID NO: 157, SEQ ID NO: 190 and SEQ ID NO: 437.

32. A method for treatment of pul monary arterial hypertension (PAH) in a human subject in need thereof, comprising: administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the composition comprises a soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide, a linker and a heterologous sequence, wherein the ALK61902004-0002-004-W01ECD polypeptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an ALK6 ECD sequence selected from SEQ ID NO: 1, 4, 11-45, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 80, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 110, 113, 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277, 283, 286, 292, 298, 304, 310, 316, 322, 328, 334 340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 41, 418, 425, or 431.

33. The method of claim 31 or 32, wherein the ALK6 ECD 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 SEQ ID NO: 90.

34. The method of claim 31 or 32, wherein the ALK6 ECD 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 SEQ ID NO: 286.

35. A soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 130:Lysi - Lys2 - Glus - Asp4 - Glys - Glus - Ser? - This - Ala9 - Prow - Thru - Pron - Argu -Prou - Lysis - Xaais - Leun - Argis - Cysis - Xaa2o - Cys2i - Xaa22- Xaa’22- Xaa”22-Xaa23 - Xaa’23 - Xaa i - Cys25 - Pro26 - Xaa27 - Asp * - Xaa29 - Xaaso- Asnsi -- Asn32 - Xaa33 -- Cys34 - Xaais - Th ns - Xaa3? - Glyss - Xaa39 - Cys4o - Phe i - Xaa4?_ - Xaa43 - Ile 4 - G1U45 - G1U4S - Asp47 ~ Asp s - Xaa49 - Glyso - Xaasi - Xaas? - Xaass - Xaas4 - Xaass—Serss—Glys?—Cysss - Xaas - Xaaso - Xaasi—Glus?—Glys3—Sers4—Aspsi - Phess - Gln67 – Cys68 - Xaas9 - Asp?o - Xaa?i - Pro??. - Xaa?3 - Xaa?4 - Xaa?s - Xaa?6 - Arg77 - Arg?s - Xaa?9 - Ileso - Glusi - Cyss2 - Cyss3 - Xaa 4 - Xaass - Xaass - Xaas7 - Xaass - Cysss - Asiuo - Xaa9i - Xaa92 - Leu93 - Xaa94 - Pro95 - Three - Leu97 - Pro9s - Pro99 - Leuioo - Lysioi - Asms? - Argios - Aspior - Pheios - Valios - Xaaio? - Xaaios - Xaaj09 - Xaai 10 - Xaaui - Xaau?. - Xaai 13;whereinXaa16 is V or IXaa20 is V, F, K, Y, T, or A;Xaa22 is G, E, H or S;Xaa’22 is absent, G, S, or A;1902004-0002-004-W01Xaa”22 is absent or S.Xaa23 is S. H, G, or L;Xaa2?’ is absent, L orll;Xaa24 is H or S;Xaa27 is E or D;Xaa29is S or A;Xaaso is V or I;Xaa33 is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q.Xaa51 is L or E;Xaa52 is P or T;Xaas3 is V or T;Xaas4 is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60is G or K;Xaa61 is L or Y;Xaa69is R or K;Xaa7i is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76is Q or L;Xaa79 is S or T;Xaa84is T or R;Xaa85 is absent, T or E;Xaa86is R or N;Xaa87 is N or L;Xaa88 is absent, E or L;1902004-0002-004-W01Xaa$>i is K or Q;Xaa92is D or L;Xaa94 is H or Q;Xaai 07 is absent;Xaaios is absent;Xaa109 is absent;Xaano is absent;Xaa111is absent;Xaa111is absent; and,Xaam is absent.

36. The fusion protein of claim 35, wherein Xaa60 is a glycine (G) residue.

37. The fission protein of claim 35, wherein the polypeptide binds BMP 10.

38. The fusion protein of claim 35, further comprising a linker sequence.

39. The fusion protein of claim 35, further comprising a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.

40. The fusion protein of claim 35, wherein the Fc comprises the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

41. Tire fusion protein of claim 35, wherein the Fc comprises the amino acid sequence of SEQ ID NO: 106.

42. A soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 157:Xaai - Xaa2 - Xaai - Xaa i - Xaas - Xaas - Xaa? - Xaas - Xaa? - Xaaio - Xaan - Xaai2 - Xaai 3 - Xaau - Xaai 5 - Xaai6 - Leun - Argis - Cysi9 - Xa 2o - Cys2i - Xaa22 - Xaa’22 - Xa ”22 - Xaa23 - Xaa’ 23 - Xaa24 - Cys25 - Prcm - Xa 27 - Asp28 - Xaa29 - Xaaso - Asnsi - Asn32 - Xaa33 - Cys34 - Xaa35 - Thrss - Xaas? - Giyas - Xaas9 - CyS40 - Phe4i - Xaa42 - Xaa43 - lie 1 ■ - GI1145 - Glu46 - A so 47 - Asp48 - Xaa49 - Glyso - Xaasi - Xaa- ■ - Xaas3 - Xaas4 - Xaa; 5 - Serss - Glys? - Cysss - Xaas9 - Xaaso - Xaasi - Glus2 - Gly63 - Ser64 - Aspss - Phe&6 - Ghi67 - Cys68 - Xaac9 - Asp?o - Xaa?i - Pro72 - Xaa73 - Xaa74 - Xaa75 - Xaa76 - Arg77 - Arg78 - Xaa79 - Ileso - Glusi - Cyss?. - Cyss3 - Xaa84 - Xaa;; - Xa 86 - Xa 7 - Xa 8 — Cys89 — Asn?o - Xaa?i - Xaa92 — Leu93 - Xaa?4 — Pro95 — I hr96 —1902004-0002-004-W01Leu97 - Pross - Pro99 - Xaaioo - Xaaioi - Xaaio2 - Xaaios - Xaaio4 - Xaai 05 - Xaaioe - Xaaio? - Xaaiog - Xaaios - Xaano - Xaam - Xaam - Xaamwherein: Xaai is K or absent;Xa 2 is K or absent;Xaa3 is E or absent;Xaar is D or absent;Xaas is G or absent,Xaas is E or absent;Xaa? is S or absent;Xaas is T or absent;Xaas is A or absent;Xaai o is P or absent;Xaan is T or absent;Xaa is P or absent;Xaai 3 is R or absent;Xaai4 is P or absent,Xaai 5 is K, P or absent;Xaai 6 is V or absence;Xaa2o is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;Xaa22is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S;Xaa’ 2 is absent, G, S, or A;Xaa”22 is absent or S;Xaa23is S, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G;Xaa’ 23 is absent, L or II;Xaa24is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;1902004-0002-004-W01 Xaa27 is E or D;Xaa29 is S. G or A;Xaa30is V, A, G or I;Xaass is I, S or T;Xaa?5 is S. T, G, A or I;Xaa37 is D, A, G or N;Xaa39is Y, A, G or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S. A. G or Q;Xaa51is L, A, G or E;Xaa52 is P or T;Xaa53is V, A, G or T;Xaa54is V, A, G or L;Xaa₅₅ is T, G or A;Xaa59is L, M, V, F, K, A, R, N, D, C, E, Q, G, H, I, P, S, T, W, or Y;Xaaeo is G. K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T. W, or Y;Xaasi is L, Y, V, F, K, A, R, N, D, C, E, Q, G, H, I, M, P, S, T, or W;Xaa69is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76is Q or L;1902004-0002-004-W01Xaa79is S or T;Xaa84is T, R or absent;Xaa85 is absent, T or E;Xaass is R, N or absent;Xaa87is N, L or absent;Xaa88 is absent, E or L;Xaa91is K, Q or absent;Xa 92 is D, L, Y or absent;Xaa94 is H, Q or absent;Xaa100 is absent, V or L;Xaa101 is absent, V or K;Xaaio2 is absent, I or X;Xaa103 is absent, G or R;Xaaio4 is absent, P, D or A;Xaai 05 is absent or F;Xaa106is absent, F, W, Y, N, Q, K, H, D, G, E or V;Xaaio7 is absent, L, M, V, F, K, A, R, N, C, E, Q, G, H, I, P, S. T, W, or Y or D; Xaai os is absent, R, T, Q, L, K, W or G;Xaaw is absent, S or P;Xaai 10 is absent or I;Xaai 11 is absent, R or H;Xaai I?, is absent or H; andXaai 13 is absent or R.

43. The fusion protein of claim 42, wherein Xaa60 is a glycine (G) residue.

44. The fusion protein of claim 42, wherein the polypeptide binds BMP 10.1902004-0002-004-W0145. The fusion protein of claim 42, further comprising a linker sequence.

46. The fusion protein of claim 42, further comprising a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.

47. Tlie fusion protein of claim 42, wherein the Fc comprises an amino acid sequence according to SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

48. The fusion protein of claim 42, wherein the Fc comprises an amino acid sequence according to SEQ ID NO: 106.

49. The fusion protein of claim 42, wherein the ALK6 ECD sequence 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 sequence selected from any one of SEQ ID NO: 132 to 155.

50. A soluble recombinant bone morphogenetic protein receptor type-1B fusion protein comprising an ALK6 ECD polypeptide and a Fc sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 190:Lysi - Lys2 - G1U3 - Aspr - Glys - Glus - Ser? - Thrs - Ala9 - Proio - Thru - Proi2 - Argo -Pro 14 - Xaais - Xaais - Leun - Argis - Cysi9 - Xaa?.o - Cys2i - Xaa22 - Xaa’22. - Xaa”22 - Xaa23 - Xaa’23 - Xaa24 - Cys25 - Pro26 - Xaa?7 - Asp28 - Xaa29 - Xaaso - Asnsi - Asn32 - Xaa33 - Cys34 - Xaass - Thrss - Xaa37 - Glyns - Xaa39 - Cys4o - Phe4i - Xaa42 - Xaa? < - Ile44 - Glu45 - Glu46 - Asp? - Aspis - Xa;. U9 - Glyso - Xaasi - Xaas? - Xaass - Xaa.54 - Xaass - Serss - Gly57 - Cysss - Xaas9 - Xaaso - Xaasi - Glus?. - Glyss - Sers4 - Aspss - Phess - Gln67 – Cys68 - Xaas9 - Asp?o - Xaa?i - Pro?2 - Xaa?3 - Xaa?4 - Xaa?s - Xaa?6 - Arg77 - Arg?s - Xaa?9 - Ileso - Glusi - Cys82 - Cyssi - Xaas4 - Xaass - Xaass - Xaas7 - Xaass - Cys89 - Asngo - Xaa9i - Xaa9?. - Leu93 - Xaa94 - Pro95 - Thros - Leu97 - Pro9» - Pro99 - Leuwo - Lysiot - Asmo2 - Argun - Xaaio4 - Pheios - Valios - Xaaio? - Xaa108 - Xaaio9 - Xaano - Xaain - Xaam - Xaaiis;wherein Xaa15is K or P;Xaa16 is V or I;Xaa?.o is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or - Xaa22is G, H, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or S;Xaa’22 is absent, G, S, or A;1902004-0002-004-W01Xaa”22 is absent or S.Xaa23 is S. II, V, F, K, A, R, N, D, C, E, Q, I, L, M, P, T, W, Y or G;Xaa’23 is absent, L or H;Xaa24is V, F, K, A, R, N, D, C, E, Q, G, H, I, L, M, P, S, T, W, or Y;Xaa27 is E or D;Xaa 9 is S. G or A;Xaaso is V, A, G or 1;Xaa33 is I, S or T;Xaaas is S. T, G, A or I;Xaa37 is D, A, G or N;Xaa39 is Y, A, G orll;Xaa42is T or A;Xaa43 is M or 1;Xaat9 is S, A, G or Q;Xaa51is L, A, G or E;Xaa.52 is P or T;Xaas3 is V, A, G or T;Xa 54 is V, A, G or L;Xaa.55 is T, G or A;Xaas9 is L, M, V, F, K, A, R, N, D, C, E, Q, G H, I, P, S. T, W, or Y;Xaa60is G, K, V, F, A, R, N, D, C, E, Q, H, I, L, M, P, S, T, W, or Y; Xaaei is L, Y, V, F. K, A, R, N, D, C, E, Q, G, H, I, M, P, S, T, or W;Xaa69is R or K;Xaa7i is T or S;Xaa.73 is I or K;1902004-0002-004-W01Xaa74 is P or A;Xaa75is H or Q;Xaa76is Q or L;Xaa79is S or T;Xaasr is absent, T or R;Xaa85 is absent, T or E;Xaass is absent, R or N;Xaa87 is N or L;Xa ss is absent, E or L;Xaasi is absent, K or Q;Xaa92 is absent, D, Y or L;Xaa94 is absent, H or Q;Xaaio4 is D or A;Xaaio7 is absent;Xaaios is absent;Xaaio9 is absent;Xaano is absent;Xaai 11 is absent;Xaai 12 is absent; and,Xaai 13 is absent.

51. The fusion protein of claim 50, wherein Xaa60 is a glycine (G) residue.

52. The fusion protein of claim 50, wherein the polypeptide binds BMP10.

53. The fusion protein of claim 50, further comprising a linker sequence.

54. The fusion protein of claim 50, further comprising a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 81902004-0002-004-W0155. The fusion protein of claim 50, wherein the Fc sequence is according to SEQ ID NO:10, SEQ ID NO: 106 or SEQ ID NO: 107.

56. The fusion protein of claim 50, wherein the Fc sequence is according to SEQ ID NO:106.

57. The fusion protein of claim 50, wherein the ALK6 ECD sequence 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 sequence selected from any one of SEQ ID NO: 158 to 189.

58. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 ECD polypeptide and a heterologous sequence, wherein the ALK6 ECD polypeptide comprises an amino acid sequence selected from a sequence of SEQ ID NO: 437:Lx si - Lys2 - Glus - Aspt - Glys - Glue - Ser? - Thrs - Alas - Proio - Thru - Proi2 - Argi3 -Proi4 - Xaais - Xaaie - Leun - Argis - Cysis - Xaa2o - Cys2i - Xaa?2 - Xaa23 -- His 'i - Cys25 - Pro26 - Xaa? - Asp28 - Xaa29 - Xaaso- Asnsi - Asn32 - Xaass- Cx ssi - Xaass - Thrse - Xaa37- Glyss - Xaas9- Cysro - Phe4i - Xaai - Xaa s - Ile44 - Gluts - G1U46 - Asp47 - Asp48 - Xa 49 - Glyso - Xaasi - Xaas2 - Xaas3 - Xaas4 - Xaass - Sense - Glys? - Cysss - Xaas9 - Xaaeo - Xaaei - Glue? - Gly 63 - Sere4 - Aspes - Pheee - Glne? - Cyses - Xaae9 - Asp?o - Xaa?i - Pro?2 - Xaa?3 - Xaa?4 - Xaa?s - Xaa?6 - Arg77 - Arg?s - Xaa?9 - Ileso - Glusi - CyS82 - Cysss - Xaasi - Xaass - Xaase - Xaas? - Xaass - Xaas9 - Xaago - Xaa9i - Xaa9?. -Xaa93 - Xaa94- Xaa95 - Xaa96 - Xaa97 - Xaa98 - Xaa99 - Xaaioo - Xaaioi - Xaaio2 - Xaaio3 - Xaaio4 - Xaaios - Xaaioe - Xaaio? - Xaaios - Xaaio9 - Xaano - Xaam - Xaam - aanswherein: Xaa15is K or P;Xaa16is V or I;Xaaso is V, F, K or Y;Xaa?.?. is G, H or S;Xaa’22 is absent, G, S or A;Xaa23 is S. H or G;Xaa?.7 is E or D;1902004-0002-004-W01 Xaa29 is S or A;Xaaso is V or I;Xaas3 is I or T;Xaa35 is S or I;Xaa37 is D or N;Xaa39 is Y or H;Xaa42is T or A;Xaa43 is M or I;Xaa49 is S or Q;Xaa51 is L or E;Xaa52 is P or T;Xaa53 is V or T;Xaa54 is V or L;Xaa55 is T or A;Xaa59 is L or M;Xaa60 is G or K;Xaa61 is L or Y;Xaa69 is R or K;Xaa71 is T or S;Xaa73 is I or K;Xaa74 is P or A;Xaa75 is H or Q;Xaa76 is Q or L;Xaa79is S or T;1902004-0002-004-W01 Xaa84 is T or R;Xaa85 is absent, T or E;Xaa86 is R or N;Xaas? is absent, X or L;Xaa88 is absent, E or L;Xaass is absent or C;Xaa o is absent or N;Xaa9i is absent, K or Q;Xaa92 is absent, D or L;Xaa93 is absent or L;Xaa94 is absent, H or Q;Xaa95 is absent or P;Xaags is absent or T;Xaa97 is absent or L;Xaa98 is absent or P;Xaa99 is absent or P;Xaa100 is absent, V or L;Xaai 01 is absent, V or K;Xaaioz is absent, I or N;Xaaio3 is absent, G or R;Xaai 04 is absent, P, D or A;Xaa105 is absent or F;Xaaioo is absent, F or V;Xaai 07 is absent or D;1902004-0002-004-W01Xaa108 is absent or G;Xaaice is absent, S or P;Xaa110 is absent or I;Xaa111is absent, R or H;Xaam is absent or II; and,Xaa113is absent or R.

59. The fusion protein of claim 58, wherein Xaa60 is a glycine (G) residue.

60. The fusion protein of claim 58, wherein the polypeptide binds one or more of BMP6, BMP7 and / or BMP 10.

61. Tire fusion protein of claim 58, further comprising a linker sequence.

62. Tire fusion protein of claim 58, further comprising a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.

63. The fusion protein of claim 58, wherein the heterologous sequence is an Fc sequence is according to SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

64. The fusion protein of claim 63, wherein the Fc sequence is according to SEQ ID NO:106.

65. The fusion protein of claim 58, wherein the ALK6 ECD sequence comprises an amino acid sequence that is at least 70%, 75%, 80*To, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence selected from any one of SEQ ID NO: 90, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425 and 431.

66. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising an ALK6 extracellular domain (ECD) polypeptide and a heterologous sequence, wherein the ALK6 ECD 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 an ALK6 ECD sequence selected from SEQ ID NO: 132-156, 158-189, 191-194, 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277 and 283.

67. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence comprises an amino acid sequence that is at least1902004-0002-004-W0170%, 75%. 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an ALK6 ECD sequence selected from SEQ ID NO: 202, 213, 218, 223, 228, 233, 242, 247, 252, 257, 262, 272, 277 and 283.

68. A soluble recombinant bone morphogenetic protein receptor type-lB fission protein comprising: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence selected from SEQ ID NO: 90, 286, 292, 298, 304, 310, 316, 322, 328, 334340, 346, 352, 358, 364, 370, 376, 382, 388, 394, 400, 406, 412, 418, 425 and 431.

69. A soluble recombinant bone morphogenetic protein receptor type-lB fission protein comprising: an ALK6 extracellular domain (ECD) and a heterologous sequence wherein the ALK6 ECD sequence 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 an ALK6 ECD sequence according to SEQ ID NO: 286.

70. Tire fission protein of claim 66-69, wherein the polypeptide binds BMP6, BMP7 and / or BMP 10.

71. The fissiosi protein of claim 66-70, further comprissng a linker sequence.

72. The fusion protein of claim 66-71, further comprising a linker sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.

73. The fusion protein of claim 66-72, wherein the heterologous sequence is a Fc sequence is according to SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

74. Tire fission protein of claim 73, wherein the Fc sequence is according to SEQ ID NO:106.

75. A soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence 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 SEQ ID NO: 203- 212, 214-217, 219-222, 224-227, 229-232, 234-241, 243-246, 248-251, 253-256, 258- 261, 263-266, 268-271, 273-276, 278-282 and 284.1902004-0002-004-W0176. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence 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 SEQ ID NO: 91, 287, 293, 299, 305, 311, 317, 323, 329, 335, 341, 347, 353, 359, 365, 371, 377, 383, 389, 395, 401, 407, 413, 419, 426 and 432.

77. A soluble recombinant bone morphogenetic protein receptor type-lB fusion protein comprising: an ALK6 extracellular domain (ECD), a linker sequence and a heterologous sequence wherein the fusion protein sequence 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 SEQ ID NO: 287.

78. The fusion protein of claim 75-77, wherein the linker sequence is according to SEQ ID NO: 6.

79. The fusion protein of claim 75-78, wherein the heterologous sequence is an Fc sequence according to SEQ ID NO: 106.

80. The fusion protein of any one of claims 35-79, wherein the ALK6 ECD polypeptide is present as a homodimer.

81. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein composing:(i) an ALK6 extracellular domain (ECD);(ii) a linker sequence; and,(iii)an Fc domain sequence;wherein the ALK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 286, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained binding to BMP 10.

82. The fusion protein of claim 81, wherein the ALK6 fusion protein demonstrates BMP10 binding comparable to SEQ ID NO: 49.

83. Tire fusion protein of claim 81, wherein the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein.1902004-0002-004-W0184. The fusion protein of claim 89, wherein the ALK6 fusion protein demonstrates an nM ICso value of about 7.2 for BMP 10 binding.

85. Tire fusion protein of claim 81, wherein the ALK6 fusion protein demonstrates an nM IC50 value of about 4.8 for BMP7 binding.

86. A soluble recombinant bone morphogenetic protein receptor type- IB fusion protein composing:(i) an ALK6 extracellular domain (ECD);(ii) a linker sequence; and,(iii) an Fc domain sequence;wherein the fusion protein sequence comprises or consists of 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 an ALK6 fusion protein sequence of SEQ ID NO: 287, w'herein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding.

87. The fusion protein of claim 86, wherein the ALK6 fusion protein demonstrates BMP10 binding comparable to SEQ ID NO: 49.

88. Tire fusion protein of claim 86, wherein the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein.

89. The fusion protein of claim 86, w'herein the ALK6 fusion protein demonstrates an nM ICso value of about 7.2 for BMP 10 binding.

90. The fusion protein of claim 86, wherein the ALK6 fusion protein demonstrates an nM ICso value of about 4.8 for BMP7 binding.

91. The fusion protein of any one of claims 35-90, w'herein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding.

92. The fusion protein of any one of claims 35-91, wherein the ALK6 fusion protein demonstrates BMP10 binding comparable to SEQ ID NO: 49.

93. The fusion protein of any one of claims 35-92, w herein the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wl) Fc fusion protein.

94. Tire fusion protein of any one of claims 35-93, w herein the ALK6 fusion protein demonstrates an nM ICso value of about 7.2 for BMP10 binding.1902004-0002-004-W0195. The fusion protein of any one of claims 35-94, wherein the ALK6 fusion protein demonstrates an nM ICso value of about 4.8 for BMP7 binding.

96. Tire fusion protein of any one of claims 35-95, wherein the linker sequence comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.

97. The fusion protein of any one of claims 35-95, wherein the Fc sequence comprises an amino acid sequence selected from SEQ ID NO: 10, SEQ ID NO: 106 or SEQ ID NO: 107.

98. A pharmaceutical composition comprising a fusion protein according to any one of 35-97; and, at least one pharmaceutical acceptable carrier or buffer.

99. Tire pharmaceutical composition of claim 98, wherein the ALK6 ECD polypeptide is present as a homodimer.

100. Use of a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising:(i) an ALK6 extracellular domain (ECD);(ii) a linker sequence; and,(iii) an Fc domain sequence;wherein the ALK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 286, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding.

101. Use of a soluble recombinant bone morphogenetic protein receptor type- IB fusion protein for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising:(i) an ALK6 extracellular domain (ECD);(ii) a linker sequence; and,(iii) an Fc domain sequence;wherein the ALK6 Fc fusion protein sequence comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,1902004-0002-004-W0192%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an ALK6 Fc fission sequence of SEQ ID NO: 287, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP 10 binding.

102. Use of a soluble recombinant bone morphogenetic protein receptor type-lB fusion protein for treatment of vascular inflammation in a human subject in need thereof, comprising administering an effective amount of the fusion protein, comprising:(i) an ALK6 extracellular domain (ECD);(ii) a linker sequence; and,(iii) an Fc domain sequence;wherein the ALK6 ECD sequence comprises or consists of 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 an ALK6 ECD sequence of SEQ ID NO: 437, wherein the position corresponding to position 60 of SEQ ID NO: 69 is a glycine (G) residue, and wherein the ALK6 fusion protein demonstrates retained BMP10 binding,103. The use of any one of claims 100-102, wherein the ALK6 fusion protein demonstrates BMP10 binding comparable to SEQ ID NO: 49.

104. The use of any one of claims 100-103, wherein the ALK6 fusion protein demonstrates BMP 10 binding comparable to binding of an ALK6 wildtype (wt) Fc fusion protein.

105. The use of any one of claims 100-104, wherein the ALK6 fusion protein demonstrates an nM ICso value of about 7,2 for BMP10 binding.

106. The use of any one of claims 100-105, wherein the ALK6 fusion protein demonstrates an nM ICso value of about 4.8 for BMP7 binding.

107. The use of any one of claims 100-106, wherein the vascular inflammation is pulmonary arterial hypertension (PAH).

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