TGF-beta receptor type II fusion proteins and uses thereof

Abstract

In certain aspects, the present disclosure relates to TRII fusion polypeptides comprising a heterologous portion and a truncated, ligand-binding portion of the extracellular domain of TBRII polypeptide useful to selectively antagonize a TRII ligand. The disclosure 5 further provides compositions and methods for use in treating or preventing TGFB associated disorders. 20 24 20 50 45 24 J ul 2 02 4 A B S T R A C T 2 0 2 4 2 0 5 0 4 5 2 4 J u l 2 0 2 4

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of Australian Application No. 2023200218 filed 17 5 January 2023, which is a divisional of Australian Application No. 2018261131 filed 3 May 2018, is related to PCT / US2018 / 030816, and claims the benefit of priority from U.S. Provisional Application No. 62 / 501,229 filed on 4 May 2017; from U.S. Provisional Application No. 62 / 510,422 filed on 24 May 2017; and from U.S. Provisional Application No. 62 / 578,674, filed on 30 October 2017. The foregoing applications are incorporated herein 10 by reference in their entirety. BACKGROUND OF THE INVENTION Members of the transforming growth factor-beta (TGFP) superfamily are pleiotropic cytokines involved in essential cellular functions such as proliferation, differentiation, 15 apoptosis, motility, extracellular matrix production, tissue remodeling, angiogenesis, immune response, cell adhesion, and also play a key role in pathophysiology of disease states as different as chronic inflammatory conditions and cancer. Members of the TGFP superfamily have been classified into major family groupings, which include TGFPs, bone morphogenetic proteins (BMP), osteogenic proteins (OP), growth and differentiation factors (GDF), 20 inhibins / activins, mullerian inhibitory substances (MIS) and glial derived neurotrophic factors (GDNF). TGFP superfamily members transduce their signals across the plasma membrane by inducing the formation of heteromeric complexes of specific type I and type II serine / threonine kinase receptors, which in turn activate a particular subset of SMAD proteins 25 (some inhibitory and some excitatory). The SMAD molecule compounds relay the signals into the nucleus where they direct transcriptional responses in concert with other proteins. Dysfunctional TGFP superfamily signaling has been linked to several clinical disorders including cancer, fibrosis, bone diseases, diabetic nephropathy, as well as chronic vascular diseases such as atherosclerosis. 30          Thus, it is an object of the present disclosure to provide compositions and methods for modulating TGFP superfamily signaling. 2024205045   24 Jul 2024 SUMMARY OF THE INVENTION In part, the disclosure provides T^RII polypeptide fusion proteins and the use of such fusion proteins as selective antagonists for TGFpi or TGFP3. As described herein, 5 polypeptides comprising part or all of the T^RII extracellular domain (ECD), with or without -la- 2024205045   24 Jul 2024 additional mutations, bind to and / or inhibit TGFpl or TGFp3 with varying affinities. In particular, TpRII polypeptides comprising a heterologous portion (e.g., an Fc immunoglobulin domain) and a linker of at least 10 amino acids in length (e.g.. a linker having the amino acid sequence of SEQ ID NO: 6) are associated with surprisingly superior 5 TGFpl and TGFP3 binding properties as compared to TpRII polypeptides having a shorter linker. Thus, in certain aspects, the disclosure provides TpRII polypeptides for use in selectively inhibiting TGFp superfamily associated disorders. In some embodiments, the disclosure provides for a Transforming Growth Factor-P Receptor II (TpRII) fusion polypeptide comprising: a) an extracellular domain of a TpRII 10 portion; b) a heterologous portion, and c) a linker portion; wherein the linker is at least 10 amino acids in length; and wherein the TpRII extracellular domain portion comprises an amino acid sequence at least 80% identical to: i) a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1 or ii) a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of 15 positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 90% identical to a sequence beginning at any of 20 positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at 25 least 97% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion comprises an amino acid 30 sequence at least 80% identical to a sequence beginning at tiny of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII 2024205045   24 Jul 2024 extracellular domain portion comprises an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 80% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 90% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 95% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion comprises an amino acid sequence at least 97% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpR11 extracellular domain portion consists of an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion consists of an ammo acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: I. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion consists of an ammo acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 2024205045   24 Jul 2024 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion consists of an amino 5 acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2. In some embodiments, the TpRII extracellular domain portion 10   consists of an amino acid sequence at least 80% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 90% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion consists of an amino acid sequence at least 95% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion consists of an amino acid 15 sequence at least 97% identical to SEQ ID NO: 18. In some embodiments, the TpRII extracellular domain portion consists of the amino acid sequence of SEQ ID NO: 18. In some embodiments, the polypeptide comprises an N-terminal leader sequence. In some embodiments, the N-terminal leader sequence comprises the amino acid sequence of any one of SEQ ID NOs: 22-24. In some embodiments, the N-terminal leader sequence comprises the 20 amino acid sequence of SEQ ID NO: 23. In some embodiments, the heterologous portion is an immunoglobulin Fc domain. In some embodiments, the immunoglobulin Fc domain is a human immunoglobulin Fc domain. In some embodiments, the heterologous portion comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 20. In some embodiments, the heterologous portion comprises an amino acid sequence that is at least 90% 25 identical to SEQ ID NO: 20. In some embodiments, the linker is less than 25 ammo acids in length. In some embodiments, the linker is between 10 and 25 amino acids in length. In some embodiments, the linker is between 15 and 25 amino acids in length. In some embodiments, the linker is between 17 and 22 amino acids in length. In some embodiments, the linker is 21 ammo acids in length. In some embodiments, the heterologous portion 30 comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 20. In some embodiments, the heterologous portion comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 20. In some embodiments, the heterologous portion comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the linker comprises (GGGGS)n, wherein n == > 2. In some embodiments, the linker comprises (GGGGS)n, 2024205045   24 Jul 2024 wherein n = > 3. In some embodiments, the linker comprises (GGGGS)n, wherein n = > 4. In some embodiments, the linker comprises (GGGGS)n, wherein n# > 5. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the linker comprises the amino acid sequence of any one of SEQ ID NOs: 4-7. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, die polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 53. In -5- 2024205045   24 Jul 2024 some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, the polypeptide comprises an ammo acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the TpRII polypeptide does not include amino acids 185-592 of SEQ ID NO: 2. In some embodiments, the TpRII polypeptide does not include amino acids 1-22 of SEQ ID NO: 2. In some embodiments, the polypeptide consists of or consists essentially of: a) a TpRII polypeptide portion comprising an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids; b) a linker portion comprising an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 6 and no more than 5, 4, 3, 2 or 1 additional amino acids; c) a heterologous portion comprising an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids; and d) optionally a leader sequence (e.g., SEQ ID NO: 23). In some embodiments, the polypeptide consists of or consists essentially of: a) a TpRII polypeptide portion comprising the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids; b) a linker portion comprising the amino acid sequence of SEQ ID NO: 6 and no more than 5, 4, 3, 2 or 1 additional amino acids; c) a heterologous portion comprising the amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids; and d) optionally a leader sequence {e.g., SEQ ID NO: 23). In some embodiments, tire polypeptide comprises: a) an extracellular domain of a TpRII portion; wherein the extracellular domain comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the sequence of SEQ ID NO: 18; b) a heterologous portion, wherein tire 2024205045   24 Jul 2024 heterologous portion comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the sequence of SEQ ID NO: 20; and c) a linker portion connecting the extracellular domain and the heterologous portion; wherein the linker comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid 5 sequence of SEQ ID NO: 6. In some embodiments, the polypeptide comprises: a) an extracellular domain of a TpRII portion; wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 18; b) a heterologous portion, wherein the heterologous portion comprises the amino acid sequence of SEQ ID NO: 20; and c) a linker portion connecting the extracellular domain and the heterologous portion; wherein the linker 10 comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the polypeptide comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the polypeptide does not include a leader sequence, or wherein the leader sequence has been 15 removed. In some embodiments, the polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a famesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an ammo acid conjugated to an organic derivatizing agent. In some embodiments, the polypeptide is glycosylated. In some embodiments, the polypeptide has a 20 glycosylation pattern characteristic of expression of the polypeptide in CHO cells. In some embodiments, the polypeptide binds human TGFpi with an equilibrium dissociation constant (KD) less than 100 pM. In some embodiments, the polypeptide binds human TGFpi with an equilibrium dissociation constant (KD) less than 75 pM. In some embodiments, the polypeptide binds human TGFp3 with an equilibrium dissociation constant (KD) less than 60 25 pM. In some embodiments, the polypeptide binds human TGFP3 with an equilibrium dissociation constant (KD) less than 50 pM. In some embodiments, the polypeptide inhibits TGFpi with an IC50 of less than 1.0 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFpi with an IC50 of less than 0.25 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits 30 TGFpi with an IC50 of less than 0.1 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFpi with an 1C50 of less than 0.05 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFP3 with an IC50 of less than 0.3 nM, as determined using a. reporter gene assay. In some embodiments, the polypeptide inhibits TGFP3 with an IC50 of less than 0.1 nM, as 2024205045   24 Jul 2024 determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFp3 with an IC50 of less than 0.05 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFP3 with an IC50 of less than 0.04 nM, as determined using a reporter gene assay. In some embodiments, the reporter gene assay is a CAGA reporter assay. In some embodiments, the disclosure provides for a homodimer comprising any two of the polypeptides disclosed herein. In some embodiments, the disclosure provides for an isolated polynucleotide comprising a coding sequence for any of the polypeptides disclosed herein. In some embodiments, the disclosure provides for a recombinant polynucleotide comprising a promoter sequence operably linked to any of the polynucleotides disclosed herein. In some embodiments, the polynucleotide comprises a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 97% or 100% identical to any one of SEQ ID NOs. 10, 12 or 14. In some embodiments, the disclosure provides for a cell transformed with any of the polynucleotides disclosed herein. In some embodiments, cell is a mammalian cell. In some embodiments, the cell is a CHO cell or a human cell. In some embodiments, the disclosure provides for a pharmaceutical preparation comprising pharmaceutically acceptable excipient and any of the polypeptides disclosed herein or any of the homodimers disclosed herein. In some embodiments, the disclosure provides for a method of modulating the response of a cell to a TGFp superfam ily member, the method comprising exposing the cell to any of the polypeptides disclosed herein or any of the homodimers disclosed herein. In some embodiments, the disclosure provides for a method of treating a disease or condition associated with a TGFp superfamily member in a patient in need thereof, the method comprising administering to the patient an effective amount of any of the polypeptides disclosed herein or any of the homodimers disclosed herein. In some embodiments, the TGFp superfamily member is TGFpl or TGFp3. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is selected from stomach cancer, intestinal cancer, skin cancer, breast cancer, melanoma, bone cancer and thyroid cancer. In some embodiments, the disease or condition is a fibrotic or sclerotic disease or condition. In some embodiments, the fibrotic or sclerotic disease or condition is selected from scleroderma, lupus erythematosis, pulmonary' fibrosis, atherosclerosis, liver fibrosis, diffuse systemic sclerosis, glomerulonephritis, neural scarring, dermal scarring, radiation-induced fibrosis, hepatic fibrosis, idiopathic pulmonary fibrosis and myelofibrosis. In some embodiments, the -8- 2024205045   24 Jul 2024 disease or condition is myelofibrosis. In some embodiments, the disease or condition is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. In some embodiments, the disease or condition is selected from the group consisting of low risk, intermediate-1 risk, intermediate-2 risk, or high-risk myelofibrosis according to the International Prognostic Scoring System (IPSS) or to the to the dynamic 1PSS (D1PSS). In some embodiments, the disease or condition is heart disease. In some embodiments, the disease or condition is selected from hereditary' hemorrhagic telangiectasia (HHT), Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, arterial tortuosity syndrome, preeclampsia, atherosclerosis, restenosis, and hypertrophic cardiomyopathy / congestive heart failure. In some embodiments, the disease or condition is pulmonary hypertension. In some embodiments, the pulmonary hypertension is Class I, Class II, Class III, or Class IV pulmonary hypertension as recognized by the World Health Organization. In some embodiments, the disease or condition is a kidney-associated disease or condition. In some embodiments, the kidney-associated disease or condition is selected from the group consisting of: chronic kidney diseases (or failure), acute kidney diseases (or failure), primary kidney diseases, non-diabetic kidney diseases, glomerulonephritis, interstitial nephritis, diabetic kidney diseases, diabetic nephropathy, glomerulosclerosis, rapid progressive glomerulonephritis, renal fibrosis, Alport syndrome, IDDM nephritis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, renal interstitial fibrosis, focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, pauci-immune rapid progressive glomerulonephritis, IgA nephropathy, polycystic kidney disease, Dent's disease, nephrocytinosis, Heymann nephritis, autosomal dominant (adult) polycystic kidney disease, autosomal recessive (childhood) polycystic kidney disease, acute kidney injury7, nephrotic syndrome, renal ischemia, podocyte diseases or disorders, proteinuria, glomendar diseases, membranous glomerulonephritis, focal segmental glomerulonephritis, pre-eclampsia, eclampsia, kidney lesions, collagen vascular diseases, benign orthostatic (postural) proteinuria, IgM nephropathy, membranous nephropathy, sarcoidosis, diabetes mellitus, kidney damage due to drugs, Fabry's disease, aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, Sickle cell disease, hemoglobinuria, myoglobinuria, Wegener's Granulomatosis, Glycogen Storage Disease Type 1, chronic kidney disease, chronic renal failure, low Glomerular Filtration Rate (GFR), nephroangiosclerosis, lupus nephritis, ANCA-positive pauci-immune crescentic glomerulonephritis, chronic allograft 2024205045   24 Jul 2024 nephropathy, nephrotoxicity, renal toxicity, kidney necrosis, kidney damage, glomerular and tubular injury, kidney dysfunction, nephritic syndrome, acute renal failure, chronic renal failure, proximal tubal dysfunction, acute kidney transplant rejection, chronic kidney transplant rejection, non-IgA mesangioproliferative glomerulonephritis, postinfectious glomerulonephritis, vasculitides with renal involvement of any kind, any hereditary renal disease, any interstitial nephritis, renal transplant failure, kidney cancer, kidney disease associated with other conditions (e.g., hypertension, diabetes, and autoimmune disease), Dent's disease, nephrocytinosis, Heymann nephritis, a primary' kidney disease, a collapsing glomerulopathy, a dense deposit disease, a cryoglobulinemia-associated glomerulonephritis, an Henoch-Schonlein disease, a postinfectious glomerulonephritis, a bacterial endocarditis, a microscopic polyangitis, a Churg-Strauss syndrome, an anti-GBM-antibody mediated glomerulonephritis, amyloidosis, a monoclonal immunoglobulin deposition disease, a fibrillary glomerulonephritis, an immunotactoid glomerulopathy, ischemic tubular injury, a medication-induced tubulo-interstitial nephritis, a toxic tubulo-interstitial nephritis, an infectious tubulo-interstitial nephritis, abacterial pyelonephritis, a viral infectious tubulointerstitial nephritis which results from a polyomavirus infection or an HIV infection, a metabolic-induced tubulo-interstitial disease, a mixed connective disease, a cast nephropathy, a crystal nephropathy which may results from urate or oxalate or drug-induced cry stal deposition, an acute cellular tubulo-interstitial allograft rejection, a tumoral infiltrative disease which results from a lymphoma or a post-transplant lymphoproliferative disease, an obstructive disease of the kidney, vascul ar disease, a thrombotic microangiopathy, a nephroangiosclerosis, an atheroembolic disease, a mixed connective tissue disease, a polyarteritis nodosa, a calcineurin-inhibitor induced-vascular disease, an acute cellular vascular allograft rejection, an acute humoral allograft rejection, early renal function decline (ERFD), end stage renal disease (ESRD), renal vein thrombosis, acute tubular necrosis, acute interstitial nephritis, established chronic kidney disease, renal artery' stenosis, ischemic nephropathy, uremia, drug and toxin-induced chronic tubulointerstitial nephritis, reflux nephropathy, kidney stones, Goodpasture's syndrome, normocytic normochromic anemia, renal anemia, diabetic chronic kidney disease, IgG4-related disease, von Hippel -Lindau syndrome, tuberous sclerosis, nephronophthisis, medullary cystic kidney disease, renal cell carcinoma, adenocarcinoma, nephroblastoma, lymphoma, leukemia, hyposialylation disorder, chronic cyclosporine nephropathy, renal reperfusion injury, renal dysplasia, azotemia, bilateral arterial occlusion, acute uric acid nephropathy, hypovolemia, acute bilateral obstructive uropathy, hypercalcemic nephropathy, hemolytic uremic syndrome, acute urinary -10- 2024205045   24 Jul 2024 retention, malignant nephrosclerosis, postpartum glomerulosclerosis, scleroderma, nonGoodpasture's anti-GBM disease, microscopic polyarteritis nodosa, allergic granulomatosis, acute radiation nephritis, post-streptococcal glomerulonephritis, Waldenstrom's macroglobulinemia, analgesic nephropathy, arteriovenous fistula, arteriovenous graft, dialysis, ectopic kidney, medullary7 sponge kidney, renal osteodystrophy, solitary kidney, hydronephrosis, microalbuminuria, uremia, haematuria, hyperlipidemia, hypoalbuminaemia, lipiduria, acidosis, hyperkalemia, and edema. In some embodiments, the kidney-associated disease or condition is chronic kidney disease. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the ammo acid sequence of native precursor for the B (short) isoform of human TGFp receptor type II (h TpRII) (NP_003233.4). Solid underline indicates the mature extracellular domain (ECD) (residues 23-159), and double underline indicates valine that is replaced in the A (long) isoform. Dotted underline denotes leader (residues 1-22). Figure 2 shows the amino acid sequence of native precursor for the A (long) isoform of human TpRII (NP 001020018.1). Solid underline indicates the mature ECD (residues 23184), and double underline indicates the splice-generated isoleucine substitution. Dotted underline denotes leader (residues 1-22). Figure 3 shows a comparison of the linker sequences of five different TpRII constructs. Figures 4A and 4B show in tabular form the binding affinity between TGFpl and TGFP3 and one of several different TpRII-Fc fusion protein constructs. Figures 5A and 5C graph the results from reporter gene assays testing the affinity of TGFpl for one of several different TpRII-Fc fusion protein constructs. Figures 5B and 5D graph the results from reporter gene assays testing the affinity of the TGFP3 for one of several different TpRII-Fc fusion protein constructs. Figures 5E and 5F provide ICso data from these same experiments in tabular form. DETAILED DESCRIPTION OF THE INVENTION 1. Overview Proteins described herein are the human forms, unless otherwise specified. NCBI references for the proteins are as follows: human TpRII isoform A (hTpRIIiong), NP_001020018.1 and human TpRII isoform B (hTpRIIshon), (NP_003233.4). Sequences of 2024205045   24 Jul 2024 native TRRH proteins from human are set forth in Figures 1 and 2. In some embodiments, the TpRII proteins are from non-human animals, such as a mouse, rat, cow or monkey. The TGFp superfamily contains a variety of growth factors that share common sequence elements and structural motifs. These proteins are known to exert biological effects 5 on a large variety of cell types in both vertebrates and invertebrates. Members of the superfamily perform important functions during embryonic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. By manipulating the activity of a member of the TGFp family, 10 it is often possible to cause significant physiological changes in an organism. For example, the Piedmontese and Belgian Blue cattle breeds cany a loss-of-function mutation in the GDF8 (also called myostatin) gene that causes a marked increase in muscle mass. Grobet et al., Nat Genet. 1997, 17(1):71-4. Similarly, in humans, inactive alleles of GDF8 are associated with increased muscle mass and, reportedly, exceptional strength. Schuelke et al., 15 N Engl J Med 2004, 350:2682-8. TGF0 signals are mediated by heteromeric complexes of type I (e.g. TpRI) and type II (e.g. TpRII) serine / threonine kinase receptors, which phosphorylate and activate downstream SMAD proteins upon ligand stimulation (Massague, 2000, Nat. Rev. Mol. Cell Biol. 1:169178). Those type I and type II receptors are transmembrane proteins, composed of a ligand-20 binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine / threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. TGFp has three 25 mammalian isoforms, TGF01, TGF02 and TGF03, each with distinct functions in vivo. The binding of TGFps to TpRII is a crucial step in initiating activation of the TGFp signaling pathway, leading to phosphorylation of SMAD2, and translocation of the activated SMAD2 / SMAD4 complex to the nucleus to modulate gene expression . Thus, in certain aspects, the disclosure provides TpRII polypeptides as antagonists of 30 TGFpi or TGFP3 for use in treating various TGF01- or TGFp3-associated disorders. While not wishing to be bound to any particular mechanism of action, it is expected that such polypeptides act by binding to TGFp 1 or TGFp3 and inh ibiting the ability of these ligands to form ternary' signaling complexes. 2024205045   24 Jul 2024 The disclosure provides for fusion proteins comprising TpRII polypeptides and a heterologous portion (e.g., an Fc portion). In particular embodiments, tire TpRII portion and the heterologous portion are fused by means of a linker. As described in greater detail below, the disclosure demonstrates that TpRII-Fc fusion proteins comprising linkers of certain lengths (e.g., a linker having 21 amino acids) were surprisingly able to bind TGFp-1 and TGFP-3 with stronger affinity than TpRII-Fc fusion proteins having a linker of only four amino acids. The terms used in this specification generally have their ordinary meanings in the art, within the context of this invention 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 invention 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 the term is used. “Homologous,” in all its grammatical forms and spelling variations, refers to the relationship between two proteins that possess a “common evolutionary' origin,” including proteins from superfamilies in the same species of organism, as well as homologous proteins from different species of organism.. Such proteins (and their encoding nucleic acids) have sequence homology, as reflected by their sequence similarity, whether in terms of percent identity or by the presence of specific residues or motifs and conserved positions. 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. However, in common usage and in the instant application, the term “homologous,” when modified with an adverb such as “highly,” may refer to sequence similarity and may or may not relate to a common evolutionary' origin. “Percent (%) sequence identity” or “percent (%) identical” 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 tire 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 ammo 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 m the art can determine appropriate parameters for aligning sequences, including any -13- 2024205045   24 Jul 2024 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 5 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 10 sequence comparison parameters are set by the ALIGN-2 program and do not vary'. ^Agonize”, in all its grammatical forms, refers to the process of activating a protein and / or gene (e.g., by activating or amplifying that protein’s gene expression or by inducing an inactive protein to enter an active state) or increasing a protein’s and / or gene’s activity. “Antagonize”, in all its grammatical forms, refers to the process of inhibiting a protein 15 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. 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. 20          Numeric ranges disclosed herein are inclusive of the numbers defining the ranges. 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 25 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). 30          Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers. As used herein, the term “comprises” also encompasses the use of the narrower terms “consisting” and “consisting essentially of.” 2024205045   24 Jul 2024 The term “consisting essentially of’ is limited to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the invention(s) disclosed herein. Ure term “appreciable affinity” as used herein means binding with a dissociation 5 constant (Kd) of less than 50 nM. Ilie terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably herein to refer to chains of amino acids of any length. The chain may be linear or branched, it may comprise modified amino acids, and / or may be interrupted by nonamino acids. The terms also encompass an amino acid chain that has been modified naturally 10 or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood 15 that the polypeptides can occur as single chains or associated chains. 2. TpRII Polypeptides Naturally occurring TpRII proteins are transmembrane proteins, with a portion of the protein positioned outside the cell (the extracellular portion) and a porti on of the protein 20 positioned inside the cell (the intracellular portion). Aspects of the present disclosure encompass variant TpRII polypeptides comprising mutations within the extracellular domain and / or truncated portions of the extracellular domain of TpRII. As described above, human TpRII occurs naturally in at least two isoforms - A (long) and B (short) - generated by alternative splicing in the extracellular domain (ECD) (Figures 1 and 2 and SEQ ID NOS: 1 25 and 2). SEQ ID NO: 27, which corresponds to residues 23-159 of SEQ ID NO: 1, depicts the native full-length extracellular domain of the short isoform of TpRII. SEQ ID NO: 18, which corresponds to residues 23-184 of SEQ ID NO: 2, depicts the native full-length extracellular domain of the long isoform of TpRII. Unless noted otherwise, amino acid position numbering with regard to variants based on the TpRII short and long isoforms refers to the 30 corresponding position in the native precursors, SEQ ID NO: 1 and SEQ ID NO: 2, respectively. In certain embodiments, the disclosure provides variant TpRII polypeptides. A TpRII polypeptide of the di sclosure may bind to and inhibit the function of a TGFp superfami ly 2024205045   24 Jul 2024 member, such as but not limited to, TGFpi or TGFP3. TpRII polypeptides may include a polypeptide consisting of, or comprising, an ammo acid sequence at least 80% identical, and optionally at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a truncated ECD domain of a naturally occurring TpRII polypeptide, whose C-terminus occurs at any of 5 amino acids 153-159 of SEQ ID NO: 1. TpRII polypeptides may include a polypeptide consisting of, or comprising, an ammo acid sequence at least 80% identical, and optionally at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a truncated ECD domain of a naturally occurring TpRII polypeptide, whose C-terminus occurs at any of amino acids 178-184 of SEQ ID NO: 2. In particular embodiments, the TpRII polypeptides comprise an 10 amino acid sequence at least 80% identical, and optionally at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. Optionally, a TBRE polypeptide does not include more than 5 consecutive amino acids, or more than 10, 20, 30, 40, 50, 52, 60, 70, 80, 90, 100, 150 or 200 or more consecutive ammo acids from a sequence consisting of amino acids 160-567 of SEQ ID NO: 1 or from a 15 sequence consisting of amino acids 185-592 of SEQ ID NO: 2. In some embodiments, the TpRII polypeptide does not include amino acids 160-567 of SEQ ID NO: 1. In some embodiments, the TpRII polypeptide does not include amino acids 1-22 of SEQ ID NO: 1. In some embodiments, the TpRII polypeptide does not include amino acids 1-22 and 160-567 of SEQ ID NO: 1. In some embodiments, the TpRII polypeptide does not include amino acids 20   185-592 of SEQ ID NO: 2. In some embodiments, tlie TpRII polypeptide does not include amino acids 1-22 of SEQ ID NO: 2. In some embodiments, the TpRII polypeptide does not include amino acids 1-22 and 185-592 of SEQ ID NO: 2. Tire unprocessed TpRII polypeptide may either include or exclude any signal sequence, as well as tiny sequence N-terminal to the signal sequence. As elaborated herein, the N-terminus of the mature 25 (processed) TpRII polypeptide may occur at any of amino acids 23-35 of SEQ ID NO: 1 or 23-60 of SEQ ID NO: 2. Examples of mature TpRII polypeptides include, but are not limited to, amino acids 23-159 of SEQ ID NO: 1 (set forth in SEQ ID NO: 27), ammo acids 29-159 of SEQ ID NO: 1 (set forth in SEQ ID NO: 28), amino acids 35-159 of SEQ ID NO: 1 (set forth in SEQ ID NO: 29), amino acids 23-153 of SEQ ID NO: 1 (set forth in SEQ ID NO: 30   30), amino acids 29-153 of SEQ ID NO: 1 (set forth in SEQ ID NO: 31), amino acids 35-153 of SEQ ID NO: 1 (set forth in SEQ ID NO: 32), ammo acids 23-184 of SEQ ID NO: 2 (set forth in SEQ ID NO: 18), amino acids 29-184 of SEQ ID NO: 2 (set forth in SEQ ID NO: 33), amino acids 60-184 of SEQ ID NO: 2 (set forth in SEQ ID NO: 29), amino acids 23-178 of SEQ ID NO: 2 (set forth in SEQ ID NO: 34), ammo acids 29-178 of SEQ ID NO: 2 (set 2024205045   24 Jul 2024 forth in SEQ ID NO: 35), and amino acids 60-178 of SEQ ID NO: 2 (set forth in SEQ ID NO: 32). It will be understood by one of skill in the art that corresponding variants based on the long isoform of TpRII will include nucleotide sequences encoding the 25-amino acid insertion along with a conservative Val-Ile substitution at the flanking position C-terminal to 5 the insertion. The TpRII polypeptides accordingly may include isolated extracellular portions of TpRII polypeptides, including both tire short and the long isoforms, variants thereof (including variants that comprise, for example, no more than 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35 amino acid substitutions in the sequence corresponding to amino acids 23-159 of SEQ ID NO: I or amino acids 23-184 of SEQ ID NO: 2), fragments thereof, and fusion proteins 10 comprising any of the foregoing, but in each case preferably any of the foregoing TpRII polypeptides will retain substantial affinity for at least one of, or both of, TGFpi or TGFP3. Generally, a TpRII polypeptide will be designed to be soluble in aqueous solutions at biologically relevant temperatures, pH levels, and osmolarity. In some embodiments, the variant TpRII polypeptides of the disclosure comprise one 15 or more mutations in the extracellular domain that confer an altered ligand binding profile. A TpRII polypeptide may include one, two, five or more alterations in the amino acid sequence relative to the corresponding portion of a naturally occurring TpRII polypeptide. In some embodiments, the mutation results in a substitution, insertion, or deletion at the position corresponding to position 70 of SEQ ID NO: 1. In some embodiments, the mutation results 20 in a substitution, insertion, or deletion at the position corresponding to position 110 of SEQ ID NO: 1. Examples include, but are not limited to, an N to D substitution or a D to K substitution in the positions corresponding to positions 70 and 110, respectively, of SEQ ID NO: 1. Examples of such variant TpRII polypeptides include, but are not limited to, the sequences set forth in SEQ ID NOs: 36-39. A TpRII polypeptide may comprise a 25 polypeptide or portion thereof that is encoded by any one of SEQ ID NOs: 10, 12, 14 or 16, or silent variants thereof or nucleic acids that hybridize to the complement thereof under stringent hybridization conditions. In particular embodiments, a TpRII polypeptide may comprise a polypeptide or portion thereof that is encoded by any one of SEQ ID NO: 12, or silent variants thereof or nucleic acids that hybridize to the complemen t thereof under 30 stringent hybridization conditions. In some embodiments, the variant TpRII polypeptides of the disclosure further comprise an insertion of 36 amino acids (SEQ ID NO: 41) between the pair of glutamate residues (positions 151 and 152 of SEQ ID NO: 1, or positions 176 and 177 of SEQ ID NO: 2024205045   24 Jul 2024 2) located near die C-terminus of the human TpRII ECD. as occurs naturally in the human TpRII isoform C (Konrad et al., BMC Genomics 8:318, 2007). The disclosure further demonstrates that TpRII polypeptides can be modified to selectively antagonize TpRII ligands. The N70 residue represents a potential glycosylation 5 site. In some embodiments, the TpRII potypeptides are aglycosylated. In some embodiments, the TpRII polypeptides are aglycosylated or have reduced glycosylation at position Asnl57. In some embodiments, the TpRII polypeptides are aglycosylated or have reduced glycosylation at position Asn73. In certain embodiments, a TpRII polypeptide binds to TGFpi, and the TpRII 10 polypeptide does not show substantial binding to TGFP3. In certain embodiments, a TpRII polypeptide binds to TGFP3, and the TpRII polypeptide does not show substantial binding to TGFpi. Binding may be assessed using purified proteins in solution or in a surface plasmon resonance system, such as a Biacore™ system. In certain embodiments, a TpRII polypeptide inhibits TGFpi cellular signaling, and 15 the TpRII polypeptide has an intermediate or limited inhibitory effect on TGFP3 signaling. In certain embodiments, a TpRII polypeptide inhibits TGFp3 cellular signaling, and the TpRII polypeptide has an intermediate or limited inhibitory effect on TGFpi signaling. Inhibitory7 effect on cell signaling can be assayed by methods known in the art. Taken together, an active portion of a TpRII polypeptide may comprise amino acid 20 sequences 23-153, 23454, 23455, 23456, 23457, or 23-158 of SEQ ID NO: 1, as well as variants of these sequences starting at any of amino acids 24-35 of SEQ ID NO: 1. Similarly, an active portion of a TpRII polypeptide may comprise amino acid sequences 23-178, 23179, 23-180, 23-181, 23-182, or 23-183 of SEQ ID NO: 2, as well as variants of these sequences starting at any of amino acids 24-60 of SEQ ID NO: 2. Exemplary TpRII 25 polypeptides comprise amino acid sequences 29-159, 35-159, 23-153, 29-153 and 35-153 of SEQ ID NO: 1 or amino acid sequences 29-184, 60-184, 23-178, 29-178 and 60-178 of SEQ ID NO: 2. Variants within these ranges are also contemplated, particularly those having at least 80%, 85%, 90%, 95%, or 99% identity7 to the corresponding portion of SEQ ID NO: 1 or SEQ ID NO: 2. A TpRII polypeptide may be selected that does not include the sequence 30 consisting of amino acids 160-567 of SEQ ID NO: 1 or amino acids 185-592 of SEQ ID NO: 2. In particular embodiments, the TpRII polypeptides comprise an amino acid sequence at least 80% identical, and optionally7 at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. 2024205045   24 Jul 2024 As described above, the disclosure provides TpRII polypeptides sharing a specified degree of sequence identity or similarity to a naturally occurring TpRII polypeptide. To determine the percent identity' of two amino acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The amino acid residues at corresponding amino acid positions are then compared. When a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid "identity" is equivalent to amino acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished using a mathematical algorithm (Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New' York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New' Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New' York, 1991). In one embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com). In a specific embodiment, the following parameters are used in the GAP program: either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., etal., Nucleic Acids Res. 12(1):387 (1984)) (available at http: / / www.gcg.com). Exemplary' parameters include using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Unless otherwise specified, percent identity between two amino acid sequences is to be determined using the GAP program using a Blosum 62 matrix, a GAP weight of 10 and a length weight of 3, and if such algorithm cannot compute the desired percent identity, a -19- 2024205045   24 Jul 2024 suitable alternative disclosed herein should be selected. In another embodiment, the percent identity between two amino acid sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. Another embodiment for determining the best overall alignment between two ammo acid sequences can be determined using the FASTDB computer program based on the algorithm of Brutlag etal. (Comp. App. Biosci., 6:237-245 (1990)). In a sequence alignment the query and subject sequences are both amino acid sequences. The result of said global sequence alignment is presented in terms of percent identity. In one embodiment, amino acid sequence identity is performed using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci., 6:237-245 (1990)). In a specific embodiment, parameters employed to calculate percent identity and similarity of an amino acid alignment comprise: Matrix=PAM 150, k-tuple=2. Mismatch Penalty=l, Joining Penalty=20, Randomization Group Length=0, Cutoff Score= I, Gap Penalty=5 and Gap Size Penalty==0.05. TpRII polypeptides may additionally include any of various leader sequences at the N-terminus. Such a sequence would allow the peptides to be expressed and targeted to the secretion pathway in a eukaryotic system. See, e.g., Ernst et al., U.S. Pat. No. 5,082,783 (1992). Alternatively, a native TpRII signal sequence may be used to effect extrusion from the cell. Possible leader sequences include native leaders, tissue plasminogen activator (TPA) and honeybee mellitin (SEQ ID NOs. 22-24, respectively). Examples of TpRIT-Fc fusion proteins incorporating a TPA leader sequence include SEQ ID NOs: 11, 13, 15 and 17. Processing of signal peptides may vary depending on the leader sequence chosen, the ceil type used and culture conditions, among other variables, and therefore actual N-terminal start sites for mature TpRII polypeptides may shift by 1, 2, 3, 4 or 5 amino acids in either the N-terminal or C-terminal direction. Examples of TpRII-Fc fusion proteins include SEQ ID NOs: 11, 13, 15 and 17. It will be understood by one of skill in the art that corresponding variants based on the long isoform of TpRII will include the 25-amino acid insertion along with a conservative Val-Ile substitution at the flanking position C-terminal to the insertion. In some embodiments, any of the TpRII polypeptides disclosed herein are at least 80%, 85%, 90%, 92%, 94%, 95%, 97%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51, but lack one or more N-terminal amino acids as compared to the amino acid sequences of SEQ ID NO: 18, 27, 30, -2.0- 2024205045   24 Jul 2024 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, the TpRII polypeptide lacks the amino acid corresponding to the first amino acid (threonine) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, the TpRII polypeptide lacks the amino acids corresponding to the first and second amino acids (threonine and isoleucine, respectively) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, the TpRII polypeptide lacks the amino acids corresponding to the first, second and third amino acids (threonine, isoleucine, and proline, respectively) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, the TpRII polypeptide lacks the ammo acids corresponding to the first, second, third and fourth amino acids (threonine, isoleucine, proline, proline, respectively) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, any of the TpRII polypeptides disclosed herein are at least 80%, 85%, 90%, 92%, 94%, 95%, 97%, 99% or 100% identical to the ammo acid sequence of any one of SEQ ID NOs: 18 or 51, but lack the amino acid corresponding to the first amino acid (threonine) of SEQ ID NO: 18 or 51. In some embodiments, the TpRII polypeptide lacks the amino acids corresponding to the first and second amino acids (threonine and isoleucine, respectively) of SEQ ID NO: 18 or 51. In some embodiments, the TpRII polypeptide lacks the ammo acids corresponding to the first, second and third amino acids (threonine, isoleucine, and proline, respectively) of SEQ ID NO: 18 or 51. In some embodiments, the TpRII polypeptide lacks the amino acids corresponding to the first, second, third and fourth amino acids (threonine, isoleucine, proline, proline, respectively) of SEQ ID NO: 18 or 51. In some embodiments, the disclosure provides for a composition comprising a mixture of TpRII polypeptides, wherein the TpRII polypeptides in the composition each comprise an ammo acid sequence that is at least 80%, 85%, 90%, 92%, 94%, 95%, 97%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51; but wherein at least a portion of the TpRII polypeptides (e.g., at least 1%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%) in the composition include the amino acids corresponding to the first, second, third and fourth amino acids (threonine, isoleucine, proline and proline, respectively) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51; and wherein at least a portion of the TpRII polypeptides (e.g., at least 1%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%) in the composition lack one or more of the amino acids corresponding to the first, second, third and fourth amino acids (threonine, isoleucine, proline and proline, -21- 2024205045   24 Jul 2024 respectively) of any one of SEQ ID NOs: 18, 27, 30, 34, 36, 37, 38, 39, 48, 49 or 51. In some embodiments, the disclosure provides for a composition comprising a mixture of TpRIl polypeptides, wherein the TpRIl polypeptides are at least 80%, 85%, 90%, 92%, 94%, 95%, 97%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 18 or 51, but wherein at least 30% to 80% of the TpRIl polypeptides in the composition lack the amino acid corresponding to the first ammo acid (threonine) of SEQ ID NO: 18 or 51. In certain embodiments, the present disclosure contemplates specific mutations of the TpRIl polypeptides so as to alter the glycosylation of the polypeptide. Such mutations maybe selected so as to introduce or eliminate one or more glycosylation sites, such as O-linked or N-linked glycosylation sites. Asparagine-linked glycosylation recognition sites generally comprise a tripeptide sequence, asparagine-X-threonine (or asparagine-X-serine) (where “X” is any amino acid) which is specifically recognized by appropriate cellular glycosylation enzymes. The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the wild-type TpRIl polypeptide (for O-linked glycosylation sites), A variety of ammo acid substitutions or deletions at one or both of the first or third amino acid positions of a glycosylation recognition site (and / or amino acid deletion at the second position) results in non-glycosylation at the modified tripeptide sequence. Another means of increasing the number of carbohydrate moieties on a TpRIl polypeptide is by chemical or enzymatic coupling of glycosides to the TpRIl polypeptide. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine; (b) free carboxyl groups; (c) free sulfhydry l groups such as those of cysteine; (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline; (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan; or (f) the amide group of glutamine. These methods are described in WO 87 / 05330 published Sep. 11, 1987, and m Aplin and Wriston (1981) CRC Crit. Rev. Biochem., pp. 259-306, incorporated by reference herein. Removal of one or more carbohydrate moieties present on a TpRH polypeptide may be accomplished chemically and / or enzymatically. Chemical deglycosylation may involve, for example, exposure of the TpRIl polypeptide to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the amino acid sequence intact. Chemical deglycosylation is further described by Hakimuddin et al. (1987) Arch. Biochem. Biophys. 259:52 and by Edge et al. (1981) Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties on TpRIl polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et -2.2- 2024205045   24 Jul 2024 al. (1987) Meth. Enzymol. 138:350. Hie sequence of aTpRII polypeptide may be adjusted, as appropriate, depending on the type of expression system used, as mammalian, yeast, insect and plant cells may all introduce differing glycosylation patterns that can be affected by the amino acid sequence of the peptide. In general, TpRII polypeptides for use in humans will be expressed in a mammalian cell line that provides proper glycosylation, such as HEK293 or CHO cell lines, although other mammalian expression cell lines, yeast cell lines with engineered glycosylation enzymes, and insect cells are expected to be useful as well. This disclosure further contemplates a method of generating mutants, particularly sets of combinatorial mutants of a TpRII polypeptide, as well as truncation mutants; pools of combinatorial mutants are especially useful for identifying functional variant sequences. The purpose of screening such combinatorial libraries may be to generate, for example, TpRII polypeptide variants which can act as either agonists or antagonist, or alternatively, which possess novel activities all together. A variety of screening assays are provided below, and such, assays may be used to evaluate variants. For example, a TpRII polypeptide variant may be screened for ability to bind to a TpRII ligand, to prevent binding of a TpRII ligand to a TpRII polypeptide or to interfere with signaling caused by a TpRII ligand. The activity of a TpRII polypeptide or its variants may also be tested in a cell-based or in vivo assay, particularly any of the assays disclosed in the Examples, Combinatorially-derived variants can be generated which have a selective or generally-increased potency relative to a TpRII polypeptide comprising an extracellular domain of a naturally occurring TpRII polypeptide. Likewise, mutagenesis can give rise to variants which have serum half-lives dramatically different than the corresponding wild-type TpRII polypeptide. For example, the altered protein can be rendered either more stable or less stable to proteolytic degradation or other processes which result in destruction of, or otherwise elimination or inactivation of, a native TpRII polypeptide. Such variants, and the genes which encode them, can be utilized to alter TpRII polypeptide levels by modulating the half-life of the TpRII polypeptides. For instance, a short half-life can give rise to more transient biological effects and can allow7 tighter control of recombinant TpRII polypepti de levels within the patient. In an Fc fusion protein, mutations may be made in the linker (if any) and / or the Fc portion to alter the half-life of the protein. A combinatorial library may be produced by way of a degenerate library of genes encoding a library of polypeptides which each include at least a portion of potential TpRII polypeptide sequences. For instance, a mixture of synthetic oligonucleotides can be enzymatically ligated into gene sequences such that the degenerate set of potential TpRII -2.3- 2024205045   24 Jul 2024 polypeptide nucleotide sequences are expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g, for phage display). There are many ways by which the library of potential T'PRII polypeptide variants can be generated from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be carried out in an automatic DNA synthesizer, and the synthetic genes then be ligated into an appropriate vector for expression. The synthesis of degenerate oligonucleotides is well known in the art (see for example, Narang, SA (1983) Tetrahedron 39:3; Itakura et al, (1981) Recombinant DNA, Proc. 3rd Cleveland Sympos. Macromolecules, ed. AG Walton, Amsterdam: Elsevier pp273-289; Itakura et al., (1984) Annu. Rev. Biochem. 53:323; Itakura et al., (1984) Science 198:1056; Ike et al., (1983) Nucleic Acid Res. 11:477). Such techniques have been employed in the directed evolution of other proteins (see, for example, Scott et al., (1990) Science 249:386-390; Roberts et al., (1992) PNAS USA 89:2429-2433; Devlin et al, (1990) Science 249: 404-406; Cwirla et al, (1990) PNAS USA 87: 6378-6382; as well as U.S. Patent Nos: 5,223,409, 5,198,346, and 5,096,815). Alternatively, other forms of mutagenesis can be utilized to generate a combinatorial library'. For example, TpRH polypeptide variants can be generated and isolated from a library by screening using, for example, alanine scanning mutagenesis and the like (Ruf et al, (1994) Biochemistry 33:1565-1572; Wang et al, (1994) J. Biol. Chern. 269:3095-3099; Balint et al, (1993) Gene 137:109-118; Grodberg et al, (1993) Eur. J. Biochem. 218:597-601; Nagashima et al, (1993) J. Biol. Chern. 268:2888-2892; Lowman etal, (1991) Biochemistry 30:1083210838; and Cunningham et al, (1989) Science 244:1081-1085), by linker scanning mutagenesis (Gustin et al, (1993) Virology 193:653-660; Brown et al, (1992) Mol. Cell Biol. 12:2644-2652; McKnight et al, (1982) Science 232:316); by saturation mutagenesis (Meyers et al, (1986) Science 232:613); by PCR mutagenesis (Leung et al, (1989) Method Cell Mol Biol 1:11-19); or by random mutagenesis, including chemical mutagenesis, etc. (Miller et al, (1992) A Short Course in Bacterial Genetics, CSHL Press, Cold Spring Harbor, NY; and Greener et al, (1994) Strategies in Mol Biol 7:32-34). Linker scanning mutagenesis, particularly in a combinatorial setting, is an attractive method for identifying truncated (bioactive) forms of TpRII polypeptides. A wide range of techniques are known in the art for screening gene products of combinatorial libraries made by point mutations and truncations, and, forthat matter, for screening cDNA libraries for gene products having a certain property. Such techniques will be generally adaptable for rapid screening of the gene libraries generated by the -24- 2024205045   24 Jul 2024 combinatorial mutagenesis of TpRII polypeptides. The most widely used techniques for screening large gene libraries typically comprises cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library' of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity' facilitates relatively easy isolation of the vector encoding the gene whose product was detected. Preferred assays include TpRII ligand binding assays and ligand-mediated ceil signaling assays. In certain embodiments, the TpRII polypeptides of the disclosure may further comprise post-translational modifications in addition to any that are naturally present in the TpRII polypeptides. Such modifications include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, pegylation (polyethylene glycol) and acylation. As a result, the modified TpRII polypeptides may contain non-amino acid elements, such as polyethylene glycols, lipids, mono- or poly-saccharides, and phosphates. Effects of such non-amino acid elements on the functionality of a TpRII polypeptide may be tested as described herein for other TpRII polypeptide variants. When a TpRII polypeptide is produced in cells by cleaving a nascent form of the TpRII polypeptide, post-translational processing may also be important for correct folding and / or function of the protein. Different cells (such as CHO, HeLa, MDCK, 293, WI38, NIH-3T3 or HEK-293) have specific cellular machinery and characteristic mechanisms for such post-translational activities and may be chosen to ensure the correct modification and processing of the TpRII polypeptides. 3. Linkers The disclosure provides for TpRII fusion proteins, and in these embodiments, the TpRII portion is connected to the heterologous portion (e.g., Fc portion) by means of a linker. In some embodiments, the linkers are glycine and serine rich linkers. Oilier near neutral amino acids, such as, but not limited to, Thr, Asn, Pro and Ala, may also be used in the linker sequence. In some embodiments, the linker comprises various permutations of amino acid sequences containing Gly and Ser. In some embodiments, the linker is greater than 10 amino acids in length. In further embodiments, the linkers have a length of at least 12, 15, 20, 21, 25, 30, 35, 40, 45 or 50 amino acids. In some embodiments, the linker is less than 40, 35, 30, 25, 22 or 20 amino acids. In some embodiments, the linker is 10-50, 10-40, 10-30, 10-25, 1021, 10-15, 10, 15-25, 17-22, 20, or 21 amino acids in length. In preferred embodiments, the linker comprises the amino acid sequence GlyGlyGlyGlySer (GGGGS) (SEQ ID NO: 19), or repetitions thereof (GGGGS)n, where n > 2. In particular embodiments n > 3, or n = 3-10, The application teaches the surprising finding that proteins comprising a TpRII portion and a -25- 2024205045   24 Jul 2024 heterologous portion fused together by means of a (GGGGS)-i linker were associated with a stronger affinity for TGFpi and TGFp3 as compared to a TpRIl fusion protein where n < 4. As such, in preferred embodiments, n > 4, or n = 4-10. The application also teaches that proteins comprising (GGGGS)n linkers in which n > 4 had similar inhibitory7 properties as proteins having the (GGGGS)4 linker. As such, in some embodiments, n is not greater than 4 in a (GGGGS)n linker. In some embodiments, n === 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-8, 5-7, or 5-6. In some embodiments, n = 3, 4, 5, 6, or 7. In particular embodiments, n = 4. In some embodiments, a linker comprising a (GGGGS)n sequence also comprises an N-terminal threonine. In some embodiments, the linker is any one of the following: GGGGSGGGGS (SEQ ID NO: 21) TGGGGSGGGGS (SEQ ID NO: 4) TGGGGSGGGGSGGGGS (SEQ ID NO: 5) TGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 6) TGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 25) TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 26) or TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 40). In some embodiments, the linker comprises the amino acid sequence of TGGGPKSCDK (SEQ ID NO: 7). In some embodiments, the linker is any one of SEQ ID NOs: 21, 4-7, 25-26 or 40 lacking the N-terminal threonine. In some embodiments, the linker does not comprise the amino acid sequence of SEQ ID NO: 26 or 40. 4. Heterologous Portions In certain aspects, functional variants or modified forms of the TpRIl polypeptides include fusion proteins having at least a portion of the TpRIl polypeptides and one or more heterologous portions. Well-known examples of such heterologous portions include, but are not limited to, polyhistidine, Glu-Glu, glutathione S transferase (GST), thioredoxin, protein A, protein G, an immunoglobulin heavy chain constant region (Fc), maltose binding protein (MBP), or human serum albumin. A heterologous portion may be selected so as to confer a desired property. For example, some heterologous portions are particularly useful for isolation of the fusion proteins by affinity chromatography. For the purpose of affinity purification, relevant matrices for affinity chromatography, such as glutathione-, amylase-, and nickel- or cobalt-conjugated resins are used. Many of such matrices are available in “kit” form, such as the Pharmacia GST purification system and the QIAexpress™ system (Qiagen) useful with (HISe) fusion partners. As another example, a heterologous portion may be 2024205045   24 Jul 2024 selected so as to facilitate detection of the TpRII polypeptides. Examples of such detection domains include the various fluorescent proteins (e.g., GFP) as well as “epitope tags,” which are usually short peptide sequences for which a specific antibody is available. Well known epitope tags for which specific monoclonal antibodies are readily available include FLAG, influenza virus haemagglutinin (HA), and c-myc tags. In some cases, the heterologous portions have a protease cleavage site, such as for Factor Xa or Thrombin, which allows the relevant protease to partially digest the fusion proteins and thereby liberate the recombinant proteins therefrom. The liberated proteins can then be isolated from the heterologous portion by subsequent chromatographic separation. In certain preferred embodiments, a TpRII polypeptide is fused with a domain that stabilizes the TpRII polypeptide in vivo (a “stabilizer” domain). By “stabilizing” is meant anything that increases serum half life, regardless of whether this is because of decreased destruction, decreased clearance by the kidney, or other pharmacokinetic effect. Fusions with the Fc portion of an immunoglobulin are known to confer desirable pharmacokinetic properties on a wide range of proteins. Likewise, fusions to human serum albumin can confer desirable properties. Other types of heterologous portions that may be selected include multimerizing (e.g., dimerizing, tetramerizing) domains and functional domains. As specific examples, the present disclosure provides fusion proteins comprising variants of TpRII polypeptides fused to an Fc domain sequence of SEQ ID NO: 20. Optionally, tire Fc domain has one or more mutations at residues such as Asp-265, Lys-322, and Asn-434 (numbered in accordance with the corresponding full-length IgG). In certain cases, the mutant Fc domain having one or more of these mutations (e.g., Asp-265 mutation) has reduced ability of binding to the Fey receptor relative to a wildtype Fc domain. In other cases, die mutant Fc domain having one or more of these mutations (e.g., Asn-434 mutation) has increased ability of binding to the MHC class I-related Fc-receptor (FcRN) relative to a wildtype Fc domain. It is understood that different elements of the fusion proteins may be arranged in any manner that is consistent with the desired functionality. For example, a TpRII polypeptide may be placed C-terminal to a heterologous domain, or, alternatively, a heterologous domain may be placed C-terminal to a TpRII polypeptide. The TpRII polypeptide domain and the heterologous domain need not be adjacent in a fusion protein, and additional domains or amino acid sequences may be included C~ or N-terminal to either domain or between the domains. 2024205045   24 Jul 2024 As used herein, the term "immunoglobulin Fc domain" or simply “Fc” is understood to mean the carboxyl-terminal portion of an immunoglobulin chain constant region, preferably an immunoglobulin heavy chain constant region, or a portion thereof. For example, an immunoglobulin Fc region may comprise 1) a CHI domain, a CH2 domain, and 5 a CH3 domain, 2) a CHI domain and a CH2 domain, 3) a CHI domain and a CH3 domain, 4) a CH2 domain and a CH3 domain, or 5) a combination of two or more domains and an immunoglobulin hinge region. In a preferred embodiment the immunoglobulin Fc region comprises at least an immunoglobulin hinge region a CH2 domain and a CH3 domain, and preferably lacks the CHI domain. In some embodiments, the immunoglobulin Fc region is a 10 human immunoglobulin Fc region. In one embodiment, the class of immunoglobulin from which the heavy chain constant region is derived is IgG (Igy) (y subclasses 1, 2, 3, or 4). Oilier classes of immunoglobulin, IgA (Iga), IgD (Ig5), IgE (Ige) and IgM (Igu), may be used. The choice of appropriate immunoglobulin heavy chain constant region is discussed in detail in U.S. Pat. 15 Nos. 5,541,087 and 5,726,044. The choice of particular immunoglobulin heavy chain constant region sequences from certain immunoglobulin classes and subclasses to achieve a particular result is considered to be within the level of skill in the art. The portion of the DNA construct encoding the immunoglobulin Fc region preferably comprises at least a portion of a hinge domain, and preferably at least a portion of a CHj domain of Fc gamma or 20 the homologous domains in any of IgA, IgD, IgE, or IgM. Furthermore, it is contemplated that substitution or deletion of amino acids within the immunoglobulin heavy chain constant regions may be useful in the practice of the methods and compositions disclosed herein. One example would be to introduce amino acid substitutions in the upper CH2 region to create an Fc variant with reduced affinity for Fc 25 receptors (Cole et al. (1997) J. Immunol. 159:3613). In some embodiments, the disclosure provides for TpRII polypeptides fusion proteins comprising an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 11, 13, 15 and 17, or biologically active fragments thereof. In some embodiments, the TpRII polypeptides fusion 30 proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 11, 13, and 15, or biologically active fragments thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 2024205045   24 Jul 2024 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 13, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 50, or a biologically active fragment thereof In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 51, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 52, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the ammo acid sequence of any one of SEQ ID NO: 53, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 54, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 55, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion proteins comprise an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 56, or a biologically active fragment thereof. In some embodiments, the TpRII polypeptides fusion protein comprises an ammo acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20, or a biologically active fragment thereof. In some embodiments, the fusion proteins described herein have improved binding affinity for TGFpl and TGFP3. In some embodiments, a fusion protein comprising a linker at least 10 ammo acids in length (e.g., a fusion protein having the amino acid sequence of any one of SEQ ID NOs: 11, 13, 15, and 50-56,) has improved binding affinity for TGFpi and TGFp3 as compared to a reference fusion protein (e.g., a fusion protein having the amino acid sequence of SEQ ID NO: 9). In some embodiments, the fusion protein binds to TGFp l with a Kn of less than 200 pM, less than 150 pM, less than 100 pM, less than 75 pM, less than 50 pM or less than 25 pM. In some embodiments, the fusion protein binds to TGFP3 with a Kd -2.9- 2024205045   24 Jul 2024 of less than 75 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 35 pM, less than 25 pM, less than 15, less than 10, or less than 5 pM. In some embodiments any of the polypeptides disclosed herein inhibits TGFpl and / or TGFp3 in a measurable assay. In some embodiments, the polypeptide inhibits TGFpi with 5 an ICso of less than 1.0, 0.9, 0.8. 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.08, 0.09, 0.07, 0.06, 0.05, 0.04, 0.03, or 0.02 nM, as determined using a reporter gene assay. In some embodiments, the polypeptide inhibits TGFP3 with an ICso of less than 1.0, 0.9, 0.8. 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, or 0.02 nM, as determined using a reporter gene assay. In some embodiments, the reporter gene assay is a CAGA reporter assay. In some 10 embodiments, the CAGA assay is based on a human lung carcinoma cell line transfected with apGL3(CAGA)12 reporter plasmid (Dennler et al, 1998, EMBO 17: 3091-3100) as well as a Renilla reporter plasmid (pRLCMV) to control for transfection efficiency. The CAGA motif is present in the promoters of TGFp-responsive genes (for example, PAI-1), so this vector is of general use for factors signaling through SMAD2 and SMAD3. See, e.g., Example 2. 15 5. Fusion Polypeptides MWWWWWWWWVWWWWWWWWWWVWWWWM In some embodiments, the disclosure provides for TpRII-containing fusion polypeptides. The fusion polypeptides may be prepared according to any of the methods disclosed herein or that are known in the art. 20          In some embodiments, any of the fusion polypeptides disclosed herein comprises the following components: a) any of the TpRII polypeptides disclosed herein (“A”), b) any of the linkers disclosed herein (“B”), c) any of the heterologous portions disclosed herein (“C”), and optionally a linker (“X”). In such embodiments, the fusion polypeptide may be arranged in a manner as follows (N-terminus to C-terminus): A-B-C or C-B-A. In such embodiments, the 25 fusion polypeptide may be arranged in a manner as follows (N-terminus to C-terminus): X-A-B-C or X-C-B-A. In some embodiments, the fusion polypeptide comprises each of A, B and C (and optionally a leader sequence such as tire ammo acid sequence of SEQ ID NO: 23), and comprises no more than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as 30 PEGylation). In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follows (N-terminus to C-terminus): X-A-B-C, and the fusion polypeptide comprises I, 2, 3, 4, or 5 ammo acids between X and A. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) 2024205045   24 Jul 2024 positioned in a manner as follows (N-terminus to C-terminus): X-C-B-A, and the fusion polypeptide comprises 1, 2, 3, 4, or 5 amino acids between X and C. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follows (N-terminus to C-terminus): X-A-B-C, and the fusion polypeptide comprises an alanine between X and A. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follows (N-terminus to C-terminus): X-C-B-A, and the fusion polypeptide comprises an alanine between X and C. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned m a manner as follows (N-terminus to C-terminus): X-A-B-C, and the fusion polypeptide comprises a glycine and an alanine between X and A. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follows (N-terminus to C-terminus): X-C-B-A, and the fusion polypeptide comprises a glycine and an alanine between X and C. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follows (N-terminus to C-terminus): X-A-B-C, and the fusion polypeptide comprises a threonine between X and A. In some embodiments, the fusion polypeptide comprises a leader sequence (e.g., SEQ ID NO: 23) positioned in a manner as follow7s (N-terminus to C-terminus): X-C-B-A, and the fusion polypeptide comprises a threonine between X and C. In some embodiments, the fusion polypeptide comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the T'PRII polypeptide amino acid sequences disclosed herein (e.g., SEQ ID NO: 18), wherein the TpRII polypeptide portion of the fusion polypeptide comprises no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the fusion polypeptide comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the linker sequences disclosed herein (e.g., SEQ ID NO: 6), wherein the linker portion of the fusion polypeptide comprises no more than 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the fusion polypeptide comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the heterologous portion sequences disclosed herein (e.g., SEQ ID NO: 20), wherein the heterologous portion of the fusion polypeptide comprises no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the fusion polypeptide comprises -31- 2024205045   24 Jul 2024 any of the TpRII polypeptide amino acid sequences disclosed herein (e.g., SEQ ID NO: 18), wherein the TpRII polypeptide portion of the fusion polypeptide comprises no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the fusion polypeptide comprises any of the linker sequences disclosed herein (e.g., SEQ ID NO: 6), wherein the linker portion of the fusion polypeptide comprises no more than 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the fusion polypeptide comprises any of the heterologous portion sequences disclosed herein (e.g., SEQ ID NO: 20), wherein the heterologous portion of the fusion polypeptide comprises no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation). In some embodiments, the disclosure provides for a fusion polypeptide, wherein the fusion polypeptide consists or consists essentially of (and not necessarily in the following order): a) an ammo acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the TpRII polypeptide amino acid sequences disclosed herein (e.g., SEQ ID NO: 18), wherein the TpRII polypeptide portion of the fusion polypeptid e compri ses no m ore than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); b) an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the linker sequences disclosed herein (e.g., SEQ ID NO: 6), wherein the linker portion of the fusion polypeptide comprises no more than 5, 4, 3, 2 or 1 additional amino acids (but w'hich may include further post-translational modifications, such as PEGylation); and c) an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to any of the heterologous portion sequences disclosed herein (e.g., SEQ ID NO: 20), wherein the heterologous portion of the fusion polypeptide comprises no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); and d) optionally a leader sequence (e.g., SEQ ID NO: 23). In some embodiments, the disclosure provides for a fusion polypeptide, wherein the fusion polypeptide consists or consists essentially of (and not necessarily in the following order): a) any of the TpRII polypeptide amino acid sequences disclosed herein (e.g., SEQ ID NO: 18), wherein the TpRII polypeptide portion of the fusion polypeptide comprises no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); b) any of the linker sequences disclosed herein (e.g., SEQ ID NO: 6), wherein the linker portion of the -32- 2024205045   24 Jul 2024 fusion polypeptide comprises no more than 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); and c) any of the heterologous portion sequences disclosed herein (e.g., SEQ ID NO: 20), wherein the heterologous portion of the fusion polypeptide comprises no more than 25, 20, 15, 10, 5, 4, 3, 5   2, or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); and d) optionally a leader sequence (e.g., SEQ ID NO: 23). In some embodiments, the disclosure provides for a fusion polypeptide consisting of or consisting essentially of (and not necessarily in the following order): a) a TpRII 10 polypeptide portion consisting of an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); b) a linker portion consisting of an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID 15 NO: 6 and no more than 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); and c) a heterologous portion consisting of an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids (but which may include further post-translational modifications, 20 such as PEGylation); and d) optionally a leader sequence (e.g., SEQ ID NO: 23). In some embodiments, the disclosure provides for a fusion polypeptide consisting or consisting essentially of (and not necessarily in the following order): a) a TpRII polypeptide portion consisting of the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational 25 modifications, such as PEGylation); b) a linker portion consisting of the amino acid sequence of SEQ ID NO: 6 and no more than 5, 4, 3, 2 or 1 additional amino acids (but which may include further post-translational modifications, such as PEGylation); and c) a heterologous portion consisting of the amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids (but which may include further post- 30 translational modifications, such as PEGylation); and d) optionally a leader sequence (e.g., SEQ ID NO: 23). In some embodiments, the fusion protein does not comprise a leader sequence. In some embodiments, the fusion protein comprises an amino acid sequence that is at least 85%, 2024205045   24 Jul 2024 90%, 92%, 95%, 96%, 97%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48. TIPPHVQKSDVEMEAQKDEIICPSCNRTAHPLRHINNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQK SCMSNCSITSICEKPQEVCVAWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETF 5 FMCSCSSDECNDNIIFSEEYNTSNPDTGGGGSGGGGSGGGGSGGGGSTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 48). 10 In some embodiments, the disclosure provides for a TpRII fusion polypeptide wherein the polypeptide does not comprise an antibody or antigen-binding portion thereof. In some embodiments, the polypeptide does not bind with appreciable affinity to a cytokine other than a transforming growth factor beta superfamily ligand (e.g., TGFpi, TGFP2 and / or TGFP3). 15 In some embodiments, the polypeptide does not bind with appreciable affinity' to a cytokine other than TGFpi, TGFP2 and / or TGFP3. In some embodiments, the polypeptide does not bind with appreciable affinity to a cytokine other than TGFpi and / or TGFp3. In some embodiments, the polypeptide does not bind with appreciable affinity to CD4, CD8, CD25, CTLA-4, IL-10, TGFp Receptor, PD-1, PD-L1, PD-L2, RANK, RANKL, HER2 / neu, 20 EGFR1, CD20, VEGF, TNF-a, TNFR2, FoxP3, CD80, CD86, IFN-a, IFN-p, IFN-y, GITR, 4-1BB, OX-40. TLR1-10, ErbB-1, HER1, ErbB-3 / HER3, ErbB-4 / HER4, IGFR, IGFBP, IGF-1R, PDGFR, FGFR, VEGFR, HGFR, TRK receptor, ephrin receptors, AXL receptors, LTK receptors, TIE receptors, angiopoietinl, 2, ROR receptor, DDR receptor, RET receptor, KLG receptor, RYK receptor, MuSK receptor, ILpR, llaR, TNTRSF, TRAIL receptor, ARTCI, 25 alpha-actinin-4, Bcr-abl, B-RAF, caspases, beta-catenin, fibronectin, GPNMB, GDP-L, LDLR, HLA-A2, MLA-A11, HSP70, KIAA205, MART2, MUM-1, 2, 3, PAP, neo-PAP, NFYC, OGT, OS-9, pml-RARalpha fusion protein, PRDX5, PTPRK, KRAS2, NRAS, HRAS, RBAF600, SIRT2. SNRPD1, SYT-SSX1 or -SSX2 fusion protein, Triosephosphate Isomerase, BAGE, BAGE-1. BAGE-2, 3, 4, 5, GAGE-1, 2, 3, 4, 5, 6, 7, 8, GnT-V, HERV-K 30 MEL, KK-LC, KM-HN-1, LAGE, LAGE-1, CAMEL, MAGE-1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-AS, MAGE-A6, MAGE-A8, MAGE-A9, MAGE-A10. MAGE-A11, MAGE-A12, MAGE-3, MAGE-B1, MAGE-B2, MAGE-B.5. MAGE-B6, MAGE-CI, MAGE-C2, mucin 1 (MUC1), MART-l / Melan-A (MLANA), gplOO, gp!00 / Pmell7 (S1LV), tyrosinase (TYR), TRP-1, HAGE, NA-88, NY-ESO-1, NY-ESO-l / LAGE-2, SAGE, 35 Spl7. SSX-L 2, 3, 4, TRP2-1NT2, carcino-embryonic antigen (CEA), Kallikfein 4, mammaglobm-A, OA1, prostate specific antigen (PSA), prostate specific membrane antigen, 2024205045   24 Jul 2024 TRP-1 / , 75. TRP-2. AIM-2. BING-4, CPSF, cyclin DI, Ep-CAM, EpbA3, FGF-5, gp250, iCE), AFP, M-CSF, mdm-2, MUCI, p53 (TP53), PBF, FRAME, PSMA, RAGE-1. RNF43, RU2AS, SOX 10, STEAP1, survivin (BIR.CS), hTERT, telomerase, WT1, SYCPI, BRDT, SPANX, XAGE, ADAM2, PAGE-5, LIP1, CTAGE-1, CSAGE, MMA1, CAGE, BORIS, HOM-TES-85, AF15ql4, HCA66I, LDHC, MORC, SGY-1, SPO11, TPX1, NY-SAR-35, FTHLI7, NXF2 TDRD1, TEX 15, FATE, TPTE, estrogen receptors (ER), androgen receptors (AR), CD40, CD30, CD20, CD 19, CD33, CD4, CD25, CD3, CA 72-4, CA 15-3, CA 27-29, CA 125, CA 19-9, beta-human chorionic gonadotropin, 1-2 microglobulin, squamous cell carcinoma antigen, neuron-specific enolase, heat shock protein gp96, GM2, sargramostim, CTLA-4, 707-AP, ART-4, CAP-1, CLCA2, Cyp-B, HST-2, HPV proteins, EBV proteins, Hepatitis B or C virus proteins, and / or HIV proteins. In some embodiments, the disclosure provides for a TpRII fusion polypeptide wherein the polypeptide does not comprise an additional ligand binding domain in addition to the TpRII domain. In some embodiments, the polypeptide comprises a linear amino acid sequence comprising a TpRII domain and a heterologous portion (e.g., an Fc portion), but the linear amino acid sequence does not comprise any additional ligand binding domains. In some embodiments, the polypeptide comprises a linear amino acid sequence comprising a TpRII domain and an Fc portion, but the linear amino acid sequence does not comprise any additional ligand binding domains. In some embodiments, the disclosure provides for a TpRII fusion polypeptide wherein the polypeptide does not comprise multiple ligand binding domains in a single linear amino acid sequence. In some embodiments, the disclosure provides for a TpRII fusion polypeptide wherein the polypeptide does not comprise more than one continuous linker sequence in a single linear amino acid sequence. In some embodiments, the polypeptide does not comprise multiple continuous glycine and / or serine linkers (e.g., a linker comprising (GGGGS)n, wherein n = > 4) in a single linear amino acid sequence. In some embodiments, the disclosure provides for a TpRII fusion polypeptide wherein the heterologous portion is an Fc domain, and wherein only one continuous linker is covalently bound to the Fc domain. In some embodiments, the only one continuous linker comprises or consists of a (GGGGS)n linker, wherein n = > 4. 6. Nucleic Acids and Methods of Manufacture In certain embodiments, the present disclosure makes available isolated and / or purified forms of the TpRII polypeptides fusion proteins, which are isolated from, or otherwise substantially free of (e.g., at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% free -35- 2024205045   24 Jul 2024 of), other proteins and / or oilier TpRII polypeptide species. TpRII polypeptides will generally be produced by expression from recombinant nucleic acids. In certain embodiments, the disclosure includes nucleic acids encoding soluble TpRII polypeptides comprising the coding sequence for an extracellular portion of a TpRII protein. In further embodiments, this disclosure also pertains to a host cell comprising such nucleic acids. The host cell may be any prokaryotic or eukaryotic cell. For example, a polypeptide of the present disclosure may be expressed in bacterial cells such as E. coli, insect cells (e.g., using a baculovirus expression system), yeast, or mammalian cells. Other suitable host cells are known to those skilled in the art. Accordingly, some embodiments of the present disclosure further pertain to methods of producing the TpRII polypeptides. In certain aspects, the disclosure provides isolated and / or recombinant nucleic acids encoding any of the TpRII polypeptides, including fragments, functional variants and fusion proteins disclosed herein. SEQ ID NOs: 10, 12 and 14 encode variants of TpRII extracellular domain fused to an IgG Fc domain. The subject nucleic acids may be single-stranded or double stranded. Such nucleic acids may be DNA or RNA molecules. These nucleic acids may be used, for example, in methods for making TpRII polypeptides or as direct therapeutic agents (e.g., in an antisense, RNAi or gene therapy approach). In certain aspects, the subject nucleic acids encoding TpRII polypeptides are further understood to include nucleic acids that are variants of SEQ ID NOs: 10, 12 and 14. Variant nucleotide sequences include sequences that differ by one or more nucleotide substitutions, additions or deletions, such as allelic variants. In certain embodiments, the disclosure provides isolated or recombinant nucleic acid sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NOs: 10, 12 and 14. In particular embodiments, the disclosure provides isolated or recombinant nucleic acid sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 12, or fragments thereof. One of ordinary" skill in the art will appreciate that nucleic acid sequences complementary" to SEQ ID NOs: 10, 12 and 14, and variants of SEQ ID NOs: 10, 12 and 14 are also within the scope of this disclosure. In further embodiments, the nucleic acid sequences of the disclosure can be isolated, recombinant, and / or fused with a heterologous nucleotide sequence, or in a DNA library. In other embodiments, nucleic acids of the disclosure also include nucleotide sequences that hybridize under highly stringent conditions to the nucleotide sequences designated in SEQ ID NOs: 10, 12 and 14 complement sequences of SEQ ID NOs: 10, 12 and 14, or fragments thereof. As discussed above, one of ordinary skill in the art will -36- 2024205045   24 Jul 2024 understand readily that appropriate stringency conditions which promote DNA hybridization can be varied. For example, one could perform the hybridization at 6.0 x sodium chloride / sodium citrate (SSC) at about 45°C, followed by a wash of 2.0 x SSC at 50°C. For example, the salt concentration in the wash step can be selected from a low7 stringency of 5 about 2.0 x SSC at 50°C to a high stringency of about 0.2 x SSC at 50°C. In addition, the temperature in the wash step can be increased from low stringency conditions at room temperature, about 22°C, to high stringency conditions at about 65°C. Both temperature and salt may be varied, or temperature or salt concentration may be held constant while the other variable is changed. In some embodiments, the disclosure provides nucleic acids which 10   hybridize under low stringency conditions of 6 x SSC at room, temperature followed by a wash at 2 x SSC at room temperature. Isolated nucleic acids which differ from the nucleic acids as set forth in SEQ ID NOs: 10, 12 and 14 due to degeneracy in the genetic code are also within the scope of the disclosure. For example, a number of amino acids are designated by more than one triplet, 15 Codons that specify the same amino acid, or synonyms (for example, CAU and CAC are synonyms for histidine) may result in ‘"silent” mutations which do not affect tire amino acid sequence of the protein. However, it is expected that DNA sequence polymorphisms that do lead to changes in the amino acid sequences of the subject proteins will exist among mammalian cells. One skilled in the art will appreciate that these variations in one or more 20 nucleotides (up to about 3-5% of the nucleotides) of the nucleic acids encoding a particular protein may exist among individuals of a given species due to natural allelic variation. Any and all such nucleotide variations and resulting amino acid polymorphisms are within the scope of this disclosure. It wi 11 be appreciated by one of skill in the art that corresponding variants based on 25 the long isofonn of TpRII will include nucleotide sequences encoding the 25-amino acid insertion along with a conservative Val-Ile substitution at the flanking position C-terminal to the insertion. It will also be appreciated that corresponding variants based on either the long (A) or short (B) isoforms of TpRII will include variant nucleotide sequences comprising an insertion of 108 nucleotides, encoding a 36-amino-acid insertion (SEQ ID NO: 41), at the 30 same location described for naturally occurring TpRII isoform C. In certain embodiments, the recombinant nucleic acids of the disclosure may be operably linked to one or more regulator}7 nucleotide sequences in an expression construct. Regulatory nucleotide sequences will generally be appropriate to the host cell used for 2024205045   24 Jul 2024 expression. Numerous types of appropriate expression vectors and suitable regulatory' sequences are known in the art for a variety of host cells. Typically, said one or more regulatory' nucleotide sequences may include, but are not limited to, promoter sequences, leader or signal sequences, ribosomal binding sites, transcriptional start and termination 5 sequences, translational start and termination sequences, and enhancer or activator sequences. Constitutive or inducible promoters as known in the art are contemplated by the disclosure. The promoters may' be either naturally occurring promoters, or hybrid promoters that combine elements of more than one promoter. An expression construct may be present in a cell on an episome, such as a plasmid, or the expression construct may be inserted in a 10 chromosome. In a preferred embodiment, the expression vector contains a selectable marker gene to allow the selection of transformed host cells. Selectable marker genes are well known in the art and will vary with the host cell used. In certain aspects disclosed herein, the subject nucleic acid is provided in an expression vector comprising a nucleotide sequence encoding a TpRII polypeptide and 15 operably linked to at least one regulatory' sequence. Regulatory' sequences are art-recognized and are selected to direct expression of the TpRII polypeptide. Accordingly, the term regulatory' sequence includes promoters, enhancers, and other expression control elements. Exemplary regulatory sequences are described in Goeddel; Gene Expression Technology. Methods in Enzymology, Academic Press, San Diego, CA (1990). For instance, any of a wide 20 variety of expression control sequences that control the expression of a DNA sequence when operatively' linked, to it may be used in these vectors to express DNA sequences encoding a TpRII polypeptide. Such useful expression control sequences, include, for example, the early and late promoters of SV40, tet promoter, adenovirus or cytomegalovirus immediate early promoter, RSV promoters, the lac system, the trp system, the TAG or TRC system, T7 25 promoter whose expression is directed by T7 RNA polymerase, the major operator and promoter regions of phage lambda , the control regions for fd coat protein, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, e.g., Pho.5, the promoters of the yeast a-mating factors, the polyhedron promoter of the baculovirus system and other sequences known to control the expression of genes of 30 prokaryotic or eukaryotic cells or their viruses, and various combinations thereof. It should be understood that the design of the expression vector may depend on such factors as the choice of the host cell to be transformed and / or the type of protein desired to be expressed. Moreover, the vector's copy number, the ability to control that copy number and the 2024205045   24 Jul 2024 expression of any other protein encoded by the vector, such as antibiotic markers, should also be considered. A recombinant nucleic acid included in the disclosure can be produced by ligating the cloned gene, or a portion thereof, into a vector suitable for expression in either prokary otic cells, eukaryotic cells (yeast, avian, insect or mammalian), or both. Expression vehicles for production of a recombinant TpRII polypeptide include plasmids and other vectors. For instance, suitable vectors include plasmids of the types: pBR322-derived plasmids, pEMBL-derived plasmids, pEX-derived plasmids, pBTac-derived plasmids and pUC-derived plasmids for expression in prokaryotic cells, such as E. colt. Some mammalian expression vectors contain both prokaryotic sequences to facilitate the propagation of the vector in bacteria, and one or more eukaryotic transcription units that are expressed in eukaryotic cells. The pcDNAI / amp, pcDNAI / neo, pRc / CMV, pSV2gpt, pSV2neo, pSV2-dhfr, pTk2, pRSVneo, pMSG, pSVT7, pko-neo and pHyg derived vectors are examples of mammalian expression vectors suitable for transfection of eukaryotic cells. Some of these vectors are modified with sequences from bacterial plasmids, such as pBR322, to facilitate replication and drug resistance selection in both prokaryotic and eukaryotic cells. Alternatively, deri vatives of viruses such as the bovine papilloma virus (BPV-1), or Epstein-Barr virus (pHEBo, pREP-derived and p205) can be used for transient expression of proteins in eukaryotic cells. Examples of other viral (including retroviral) expression systems can be found below in the description of gene therapy delivery systems. The various methods employed in the preparation of the plasmids and in transformation of host organisms are well known in the art. For other suitable expression systems for both prokaryotic and eukaryotic cells, as well as general recombinant procedures, see Molecular Cloning A Laboratory Manual, 3rd Ed., ed. by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory' Press, 2001). In some instances, it may be desirable to express the recombinant polypeptides by the use of a baculovirus expression system. Examples of such baculovirus expression systems include pVL-derived vectors (such as pVLI392, pVL1393 and pVL941), pAcUW-derived vectors (such as pAcUWl), and pBlueBac-derived vectors (such as the B-gal containing pBlueBac III). In certain embodiments, a vector will be designed for production of the subject TpRII polypeptides in CHO cells, such as a Pcmv-Script vector (Stratagene, La Jolla, Calif.), pcDN4 vectors (Invitrogen, Carlsbad, Calif.) and pCI-neo vectors (Promega, Madison, Wise,). In a preferred embodiment, a vector will be designed for production of the subject TpRII polypeptides in HEK-293 cells. As will be apparent, the subject gene constructs can -39- 2024205045   24 Jul 2024 be used to cause expression of the subject TpRII polypeptides in cells propagated in culture, e.g., to produce proteins, including fusion proteins or variant proteins, for purification. This disclosure also pertains to a host cell transfected with a recombinant gene including a coding sequence (e.g., SEQ ID NOs: 10, 12, or 14) for one or more of the subject 5 TpRII polypeptides. Hie host cell may be any prokaryotic or eukaryotic cell. For example, a TpRII polypeptide disclosed herein may be expressed in bacterial cells such as E. coh, insect cells (e.g., using abaculovirus expression system), yeast, or mammalian cells. Other suitable host cells are known to those skilled in the art. Accordingly, the present disclosure further pertains to methods of producing the 10 subject TpRII polypeptides. For example, a host cell transfected with an expression vector encoding a TpRII polypeptide can be cultured under appropriate conditions to allow expression of the TpRII polypeptide to occur. The TpRII polypeptide may be secreted and isolated from a mixture of cells and medium containing the TpRII polypeptide. Alternatively, the TpRII polypeptide may be retained cytoplasmically or in a membrane 15 fraction and the cells harvested, lysed and the protein isolated. A cell culture includes host cells, and media. Suitable media for cell culture are well known in the art. The subject TpRII polypeptides can be isolated from cell culture medium, host cells, or both, using techniques known in the art for purifying proteins, including ion-exchange chromatography, gel filtration chromatography, ultrafiltration, electrophoresis, immunoaffinity purification 20 with antibodies specific for particular epitopes of the TpRII polypeptides and affinity purification with an agent that binds to a domain fused to the TpRII polypeptide (e.g., a protein A column may be used to purify an TpRII-Fc fusion). In a preferred embodiment, the TpRII polypeptide is a fusion protein containing a domain which facilitates its purification. As an example, purification may be achieved by a series of column chromatography steps, 25 including, for example, three or more of the following, in any order: protein A chromatography, Q sepharose chromatography, phenylsepharose chromatography, size exclusion chromatography, and cation exchange chromatography. The purification could be completed with viral filtration and buffer exchange. In another embodiment, a fusion gene coding for a purification leader sequence, such 30 as a poly-(His) / enterokinase cleavage site sequence at the N-terminus of the desired portion of the recombinant TpRII polypeptide, can allow purification of the expressed fusion protein by affinity chromatography using a Ni2f metal resin. The purification leader sequence can then be subsequently removed by treatment with enterokinase to provide the purified TpRII 2024205045   24 Jul 2024 polypeptide (e.g., see Hochuli et al., (1987) J. Chromatography 411:177; and Janknecht et A.,PNASUSA 88:8972). Techniques for making fusion genes are well known. Essentially, the joining of various DNA fragments coding for different polypeptide sequences is performed in accordance with conventional techniques, employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DMA synthesizers. Alternatively, PCR ampli fication of gene fragments can be carried out using anchor primers which give rise to complementary' overhangs between two consecutive gene fragments which can subsequently be annealed to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, eds. Ausubel et al., John Wiley & Sons: 1992). 7. Alterations in Fc-fusion proteins The application further provides TpRII-Fc fusion proteins with engineered or variant Fc regions. Such antibodies and Fc fusion proteins may be useful, for example, in modulating effector functions, such as, antigen-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Additionally, the modifications may improve the stability of the antibodies and Fc fusion proteins. Ammo acid sequence variants of the antibodies and Fc fusion proteins are prepared by introducing appropriate nucleotide changes into the DNA, or by peptide synthesis. Such variants include, for example, deletions from, and / or insertions into and / or substitutions of, residues within the amino acid sequences of the antibodies and Fc fusion proteins disclosed herein. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired characteristics. The amino acid changes also may alter post-translational processes of the antibodies and Fc fusion proteins, such as changing the number or position of glycosylation sites. Antibodies and Fc fusion proteins with reduced effector function may be produced by introducing changes in the amino acid sequence, including, but are not limited to, the Ala-Ala mutation described by Bluestone et al. (see WO 94 / 28027 and WO 98 / 47531; also see Xu et al. 2000 Cell Immunol 200; 16-26). Thus, in certain embodiments, Fc fusion proteins of the disclosure with mutations within the constant region including the Ala-Ala mutation may be used to reduce or abolish effector function. According to these embodiments, antibodies and -41- 2024205045   24 Jul 2024 Fc fusion proteins may comprise a mutation to an alanine at position 234 or a mutation to an alanine at position 235, or a combination thereof. In one embodiment, the antibody or Fc fusion protein comprises an IgG4 framework, wherein the Ala-Ala mutation would describe a mutation(s) from phenylalanine to alanine at position 234 and / or a mutation from leucine to alanine at position 235. In another embodiment, the antibody or Fc fusion protein comprises an IgGl framework, wherein the Ala-Ala mutation would describe a mutation(s) from leucine to alanine at position 234 and / or a mutation from leucine to alanine at position 235. The antibody or Fc fusion protein may alternatively or additionally carry' other mutations, including the point mutation K322A in the CH2 domain (Hezareh et al. 2001 J Virol. 75: 12161-8). In particular embodiments, the antibody or Fc fusion protein may be modified to either enhance or inhibit complement dependent cytotoxicity (CDC). Modulated CDC activity may be achieved by introducing one or more amino acid substitutions, insertions, or deletions in an Fc region (see, e.g., U.S. Pat. No. 6,194,551). Alternatively or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region. Hie homodimeric antibody thus generated may have improved or reduced internalization capability and / or increased or decreased complement-mediated cell killing. See Caron etal., J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J. Immunol. 148:2918-2922 (1992), WO99 / 51642, Duncan & Winter Nature 322: 738-40 (1988): U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821; and WO94 / 29351. 8. Screening Assays In certain aspects, the present invention relates to the use of TpRII polypeptides (e.g., soluble TpRII polypeptides) to identify compounds (agents) which are agonist or antagonists of the TGFpi, TGFp3 and TpRII signaling pathway. Compounds identified through this screening can be tested to assess their ability to modulate TGFpi and TGFP3 signaling activity in vitro. Optionally, these compounds can further be tested in animal models to assess their ability to modulate tissue growth in vivo. There are numerous approaches to screening for therapeutic agents for modulating tissue growth by targeting TGFpi, TGFP3 and TpRII polypeptides. In certain embodiments, high-throughput screening of compounds can be carried out to identify agents that perturb TGFpi, TGFP3 or TpRII-mediated cell signaling. In certain embodiments, the assay is carried out to screen and identify' compounds that specifically inhibit or reduce binding of a TpRII polypeptide to TGFpi or TGFP3. Alternatively, the assay can be used to identify -42- 2024205045   24 Jul 2024 compounds that enhance binding of a TpRII polypeptide to TGFpl or TGFP3. In a further embodiment, the compounds can be identified by their ability to interact with a TGFpl, TGFp3 or TpRII polypeptide. A variety of assay formats will suffice and, in light of the present disclosure, those not 5 expressly described herein will nevertheless be comprehended by one of ordinary skill in the art. As described herein, the test compounds (agents) of tire invention may be created by any combinatorial chemical method. Alternatively, the subject compounds may be naturally occurring biomolecules synthesized in vivo or in vitro. Compounds (agents) to be tested for their ability to act as modulators of tissue growth can be produced, for example, by bacteria, 10 yeast, plants or other organisms (e.g., natural products), produced chemically (e.g., small molecules, including peptidomimetics), or produced recombinantly. Test compounds contemplated by the present invention include non-peptidyl organic molecules, peptides, polypeptides, peptidomimetics, sugars, hormones, and nucleic acid molecules. In a specific embodiment, the test agent is a small organic molecule having a molecular weight of less 15 than about 2,000 daltons. The test compounds of the invention can be provided as single, discrete entities, or provided in libraries of greater complexity, such as made by combinatorial chemistry. These libraries can comprise, for example, alcohols, alkyl halides, amines, amides, esters, aldehydes, ethers and other classes of organic compounds. Presentation of test compounds to 20 the test system can be in either an isolated form or as mixtures of compounds, especially in initial screening steps. Optionally, the compounds may be optionally derivatized with other compounds and have derivatizing groups that facilitate isolation of the compounds. Nonlimiting examples of derivatizing groups include biotin, fluorescein, digoxygenin, green fluorescent protein, isotopes, polyhistidine, magnetic beads, glutathione S transferase (GST), 25 photoactivatible crosslinkers or any combinations thereof. In many drug screening programs which test libraries of compounds and natural extracts, high throughput assays are desirable in order to maximize the number of compounds sureeyed in a given period of time. Assays which are performed in cell-free systems, such as may be derived with purified or semi-purified proteins, are often preferred as “primary'” 30 screens in that they' can be generated to permit rapid development and relatively' easy detection of an alteration in a molecular target which is mediated by a test compound. Moreover, the effects of cellular toxicity or bioavailability of the test compound can be generally' ignored in the in vitro system, the assay instead being focused primarily on the 2024205045   24 Jul 2024 effect of tiie drug on the molecular target as may be manifest in an alteration of binding affinity between a TpRII polypeptide and TGFpi or TGFP3. Merely to illustrate, in an exemplary’ screening assay of the present invention, the compound of interest is contacted with an isolated and purified TpRII polypeptide which is ordinarily' capable of binding to TGFpi or TGFp3. To the mixture of the compound and TpRII polypeptide is then added a composition containing a TpRII ligand. Detection and quantification of TpRII / TGFpi or TPRII / TGFP3 complexes provides a means for determining the compound's efficacy' at inhibiting (or potentiating) complex formation between the TpRII polypeptide and TGFpi or TGFP3. The efficacy of the compound can be assessed by generating dose response curves from data obtained using various concentrations of the test compound. Moreover, a control assay can also be performed to provide a baseline for comparison. For example, in a control assay, isolated and a purified TGFpi or TGFP3 is added to a composition containing the TpRII polypeptide, and the formation of TpRII / TGFpi or TPRII / TGFP3 complex is quantitated in the absence of the test compound. It will be understood that, in general, the order in which the reactants may be admixed can be varied, and can be admixed simultaneously. Moreover, in place of purified proteins, cellular extracts and lysates may be used to render a suitable cell-free assay system.. Complex formation between the TpRII polypeptide and TGFp i or TGFP3 may be detected by a variety' of techniques. For instance, modulation of the formation of complexes can be quantitated using, for example, detectably labeled proteins such as radiolabeled (e.g., 32P, 35S, 14C or 3H), fluorescently' labeled (e.g., FITC), or enzymatically labeled TpRII polypeptide or TGFpi or TGFP3, by immunoassay, or by' chromatographic detection. In certain embodiments, the present invention contemplates the use of fluorescence polarization assays and fluorescence resonance energy transfer (FRET) assays in measuring, either directly or indirectly, the degree of interaction between a TpRII polypeptide and its binding protein. Further, other modes of detection, such as those based on optical waveguides (PCT Publication WO 96 / 26432 and U.S. Pat. No. 5,677,196), surface plasmon resonance (SPR), surface charge sensors, and surface force sensors, are compatible with many' embodiments of the invention. Moreover, the present invention contemplates the use of an interaction trap assay, also known as the “two hybrid assay,'’ for identifying agents that disrupt or potentiate interaction between a TpRII polypeptide and its binding protein. See for example, U.S. Pat. No. 5,283,317; Zervos etal. (1993) Cell 72:223-232; Madura et al. (1993) J Biol Chem 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; and Iwabuchi et al. (1993) -44- 2024205045   24 Jul 2024 Oncogene 8:1693-1696). In a specific embodiment, the present invention contemplates the use of reverse two hybrid systems to identify compounds (e.g., small molecules or peptides) that dissociate interactions between a TpRII polypeptide and its binding protein. See for example, Vidal and Legrain, (1999) Nucleic Acids Res 27:919-29; Vidal and Legrain, (1999) 5 Trends Biotechnol 17:374-81; and U.S. Pat. Nos. 5,525,490; 5,955,280; and 5,965,368. In certain embodiments, the subject compounds are identified by their ability to interact with a TpRII or TGFpl or TGFP3 polypeptide of the in vention. The interaction between the compound and the TpRII or TGFpi or TGFP3 polypeptide may be covalent or non-covalent. For example, such interaction can be identified at the protein level using in 10 vitro biochemical methods, including photo-crosslinking, radiolabeled ligand binding, and affinity chromatography (Jakoby WB et al., 1974, Methods in Enzymology 46: 1). In certain cases, the compounds may be screened in a mechanism based assay, such as an assay to detect compounds which bind to a TGFpl or TGFP3 or TpRII polypeptide. This may include a solid-phase or fluid-phase binding event. Alternatively, the gene encoding a TGFpl or 15 TGFP3 or TpRII polypeptide can be transfected with a reporter system (e.g., P~galactosidase, luciferase, or green fluorescent protein) into a cell and screened against the library preferably by a high-throughput screening or with individual members of the library’. Other mechanismbased binding assays may be used, for example, binding assays which detect changes in free energy. Binding assays can be performed with the target fixed to a well, bead or chip or 20 captured by an immobilized antibody or resolved by capillary electrophoresis. The bound compounds may be detected usually using colorimetric or fluorescence or surface plasmon resonance. In certain aspects, the present invention provides methods and agents for modulating (stimulating or inhibiting) TGFpi- or TGFp3-mediated cell signaling. Therefore, any 25 compound identified can be tested in whole cells or tissues, in vitro or in vivo, to confirm their ability to modulate TGFpi or TGFP3 signaling. Various methods known in the art can be utilized for this purpose. 9- Exemplary Therapeutic Uses 30          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 the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. 2024205045   24 Jul 2024 The terms "treatment", "treating", ‘‘alleviation” 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 symptoms of a condition being treated. Tire effect may be prophylactic in terms of completely or partially delaying the onset or recurrence of a disease, condition, or symptoms 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, and includes: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition (e.g., arresting its development); or (c) relieving the disease or condition (e.g., causing regression of the disease or condition, providing improvement in one or more symptoms). The terms “patient”, “subject”, or “individual” are used interchangeably herein and refer to either a human or a non-human animal. These terms include mammals, such as humans, non-human primates, laboratory animals, livestock animals (including bovines, porcines, camels, etc.), companion animals (e.g., canines, felines, other domesticated animals, etc.) and rodents (e.g., mice and rats). In particular embodiments, the patient, subject or individual is a human. Ilie disclosure provides methods of treating or preventing a disease or condition associated with a TGFp superfamily member by administering to a subject an effective amount of a TpRII polypeptide, including a TpRII-Fc fusion protein of the foregoing, hereafter collectively referred to as “therapeutic agents”. In some embodiments the disease or condition is associated with dysregulated TGFpi or TGFp3 signaling. Also provided are methods and compositions for treating certain cardiovascular or vascular disorders. In addition, the disclosure provides methods and compositions for treating or preventing cancer. In addition, the disclosure provides methods and compositions for treating or preventing fibrotic disorders and conditions. In particular, polypeptide therapeutic agents of the present disclosure are useful for treating or preventing chronic vascular or cardiovascular diseases. Exemplary disorders of this kind include, but are not limited to, heart disease (including myocardial disease, myocardial infarct, angina pectoris, and heart valve disease); renal disease (including chronic glomerular inflammation, diabetic renal failure, and lupus-related renal inflammation); disorders associated with atherosclerosis or other types of arteriosclerosis (including stroke, -46- 2024205045   24 Jul 2024 cerebral hemorrhage, subarachnoid hemorrhage, angina pectoris, and renal arteriosclerosis): thrombotic disorders (including cerebral thrombosis, thrombotic intestinal necrosis); complications of diabetes (including diabetes-related retinal disease, cataracts, diabetes-related renal disease, diabetes-related neuropathology, diabetes-related gangrene, and 5 diabetes-related chronic infection); vascular inflammatory disorders (systemic lupus erythematosus, joint rheumatism joint arterial inflammation, large-cell arterial inflammation, Kawasaki disease, Takayasu arteritis, Churg-Strauss syndrome, and Henoch-Schoenlein purpura); diabetic vasculopathies; and cardiac disorders such as congenital heart disease, cardiomyopathy (e.g., dilated, hypertrophic, restrictive cardiomyopathy), and congestive 10 heart failure. Exemplary disorders further include, but are not limited to, hereditary hemorrhagic telangiectasia (HHT), Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, arterial tortuosity syndrome, pre-eclampsia, and restenosis. The TpRII polypeptide can be administered to the subject alone, or in combination 15 with one or more agents or therapeutic modalities, e.g., therapeutic agents, which are useful for treating TGFp associated cardiovascular disorders and / or conditions. In certain embodiments, the second agent or therapeutic modality is chosen from one or more of: angioplasty, beta, blockers, anti-hypertensives, cardiotonics, anti-thrombotics, vasodilators, hormone antagonists, endothelin antagonists, calcium channel blockers, phosphodiesterase 20 inhibitors, angiotensin type 2 antagonists and / or cytokine blockers / inhibitors In particular, polypeptide therapeutic agents of the present disclosure are useful for treating or preventing a cancer (tumor). The terms “cancer” and “cancerous” refer to or describe, the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Examples of cancer, or neoplastic disorders, include 25 but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous ceil cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary? gland carcinoma, kidney cancer, 30 prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, stomach cancer, intestinal cancer, skin cancer, bone cancer, gastric cancer, melanoma, and various types of head and neck cancer, including squamous cell head and neck cancer. Other examples of neoplastic disorders and related conditions include esophageal carcinomas, thecomas, arrhenoblastomas, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, nasopharyngeal 2024205045   24 Jul 2024 carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, Wilm's 5 tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, and Meigs’ syndrome. A cancer that is particularly amenable to treatment with the therapeutic agents described herein may be characterized by one or more of the following: the cancer has elevated TpRII levels detectable in the tumor or the serum, increased TGFpl or TGFp3 expression levels or biological activity, is metastatic or at risk of 10 becoming metastatic, or any combination thereof. In certain embodiments of such methods, one or more polypeptide therapeutic agents can be administered, together (simultaneously) or at different times (sequentially). In addition, polypeptide therapeutic agents can be administered with another type of compounds for treating cancer or for inhibiting angiogenesis. 15           In certain embodiments, the subject methods of the disclosure can be used alone. Alternatively, the subject methods may be used in combination with other conventional anticancer therapeutic approaches directed to treatment or prevention of proliferative disorders (e.g., tumor). For example, such methods can be used in prophylactic cancer prevention, prevention of cancer recurrence and metastases after surgery, and as an adjuvant of other 20 conventional cancer therapy. The present disclosure recognizes that the effectiveness of conventional cancer therapies (e.g., chemotherapy, radiation therapy, phototherapy, immunotherapy, and surgery7) can be enhanced through the use of a subject polypeptide therapeutic agent. A wide array7 of conventional compounds have been shown to have anti-neoplastic or 25 anti-cancer activities. These compounds have been used as pharmaceutical agents in chemotherapy to shrink solid tumors, prevent metastases and further growth, or decrease the number of malignant cells in leukemic or bone marrow malignancies. Although chemotherapy7 has been effective in treating various types of malignancies, many antineoplastic compounds induce undesirable side effects. It has been shown that w7hen two or 30 more different treatments are combined, the treatments may work synergistically and allow reduction of dosage of each of the treatments, thereby reducing the detrimental side effects exerted by7 each compound at higher dosages. In other instances, malignancies that are refractory7 to a treatment may respond to a combination therapy of two or more different treatments. 2024205045   24 Jul 2024 When a therapeutic agent disclosed herein is administered in combination with another conventional anti-neoplastic agent, either concomitantly or sequentially, such therapeutic agent may enhance the therapeutic effect of the anti-neoplastic agent or overcome cellular resistance to such anti-neoplastic agent. This allows decrease of dosage of an anti-5 neoplastic agent, thereby reducing the undesirable side effects, or restores the effectiveness of an anti-neoplastic agent in resistant cells. According to the present disclosure, the polypeptide therapeutic agents described herein may be used in combination with other compositions and procedures for the treatment of diseases. For example, a tumor may be treated conventionally with surgery, radiation or 10 chemotherapy combined with the TpRII polypeptide, and then the TpRII polypeptide may be subsequently administered to the patient to extend the dormancy of micrometastases and to stabilize any residual primary' tumor. In certain aspects of the invention, other therapeutic agents useful for combination tumor therapy with a TpRII polypeptide include other cancer therapies: e.g., surgery', 15 cytotoxic agents, radiological treatments involving irradiation or administration of radioactive substances, chemotherapeutic agents, anti-hormonal agents, growth inhibitory agents, antineoplastic compositions, and treatment with anti-cancer agents listed herein and known in the art, or combinations thereof. Hie term "cytotoxic agent" as used herein refers to a substance that inhibits or 20 prevents the function of cells and / or causes destruction of cells. The term is intended to include radioactive isotopes (e.g., At2!!, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32 and radioactive isotopes of Lu), chemotherapeutic agents e.g, methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents, enzymes and fragments thereof such 25 as nucleolytic enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof, and the various antitumor or anticancer agents disclosed below. Other cytotoxic agents are described below'. A tumoricidal agent causes destraction of tumor cells. 30          A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, 2024205045   24 Jul 2024 trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARJNOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-1 1 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocannycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g,, Agnew, Chem Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicm, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; eifomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; 2024205045   24 Jul 2024 mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine: PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, 5 roridin A and anguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"): thiotepa; taxoids, e.g., TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® 10 doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin; ibandronate; 15 topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with 20 oxaliplatin (ELOXATIN™) combined with 5-FU and leucovovin. Also included in this definition are anti-hormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systemic, or whole-body treatment. They may be hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs), 25 including, for example, tamoxifen (including NOLVADEX® tamoxifen), EVISTA® raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON® toremifene; anti-progesterones; estrogen receptor down-regulators (ERDs); agents that function to suppress or shut down the ovaries, for example, luteinizing hormone-releasing hormone (LHRH) agonists such as LUPRON® and ELIGARD® 30 leuprolide acetate, goserelin acetate, buserelin acetate and tripterelin; other anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestane, fadrozole, R1V1S OR® vorozoie, FEMARA® letrozole, and 2024205045   24 Jul 2024 ARIMIDEX® anastrozole. In addition, such definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), DIDROC AL® etidronate, NE-58095, ZOMET A® zoledronic acid / zoledronate, FOSAMAX® alendronate, AREDIA® pamidronate, SKELID® tiludronate, or ACTONEL® risedronate; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H~Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECHN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; LURTOTECAN® topoisomerase 1 inhibitor; ABARELIX® nnRH; lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small-molecule inhibitor also known as GW572016); and pharmaceutically acceptable salts, acids or derivatives of any of the above. A "growth inhibitory’ agent" when used herein refers to a compound or composition which inhibits growth of a cell either in vitro or in vivo. Thus, the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al, (WB Saunders: Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone -Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by' preventing depolymerization, which results in the inhibition of mitosis in cells. In still other embodiments, TpRII polypeptides may' be usefill in the treatment or prevention of fibrosis. As used herein, the term "fibrosis" refers to the aberrant formation or development of excess fibrous connective tissue by cells m an organ or tissue. Although -52- 2024205045   24 Jul 2024 processes related to fibrosis can occur as part of normal tissue formation or repair, dysregulation of these processes can lead to altered cellular composition and excess connective tissue deposition that progressively impairs to tissue or organ function. The formation of fibrous tissue can result from a reparative or reactive process. Fibrotic disorders 5 or conditions include, but are not limited to, fibroproliferative disorders associated with vascular diseases, such as cardiac disease, cerebral disease, and peripheral vascular disease, as well as tissues and organ systems including the heart, skin, kidney, peritoneum., gut, and liver (as disclosed in, e.g., Wynn, 2004, Nat Rev 4:583-594, incorporated herein by reference). Exemplary disorders that can be treated include, but are not limited to, renal 10 fibrosis, including nephropathies associated with injury / fibrosis, e.g., chronic nephropathies associated with diabetes (e.g., diabetic nephropathy), lupus, scleroderma, glomerular nephritis, focal segmental glomerular sclerosis, and IgA nephropathy; gut fibrosis, e.g., scleroderma, and radiation-induced gut fibrosis; liver fibrosis, e.g., cirrhosis, alcohol-induced liver fibrosis, biliary' duct injury’, primary biliary cirrhosis, infection or viral-induced liver 15 fibrosis, congenital hepatic fibrosis and autoimmune hepatitis; and other fibrotic conditions, such as cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis,, injection fibrosis (which can occur as a complication of intramuscular injections, especially' in children), endomyocardial fibrosis, retroperitoneal fibrosis, and nephrogenic systemic 20 fibrosis. As used herein, the terms "fibrotic disorder", "fibrotic condition," and "fibrotic disease," are used interchangeably to refer to a disorder, condition or disease characterized by fibrosis. Examples of fibrotic disorders include, but are not limited to lupus, sclerotic disorders (e.g., scleroderma, atherosclerosis, and systemic scleroisis including, e.g., diffuse 25 systemic sclerosis and progressive systemic sclerosis ), vascular fibrosis, pancreatic fibrosis, liver fibrosis (e.g., cirrhosis), renal fibrosis, musculoskeletal fibrosis, cardiac fibrosis (e.g., endomyocardial fibrosis, idiopathic myocardiopathy), skin fibrosis (e.g., scleroderma, post-traumatic, operative cutaneous scarring, keloids and cutaneous keloid formation), eye fibrosis (e.g., glaucoma, sclerosis of the eyes, conjunctival and corneal scarring, and pterygium), 30 myelofibrosis, chronic graft-versus-host disease, Peyronie's disease, post-cystoscopic urethral stenosis, idiopathic and pharmacologically induced retroperitoneal fibrosis, mediastinal fibrosis, proliferative fibrosis, neoplastic fibrosis, Dupuytren's disease, strictures, neural scarring, dermal scarring, idiopathic pulmonary’ fibrosis and radiation induced fibrosis. 2024205045   24 Jul 2024 In some embodiments, any of the polypeptides disclosed herein (e.g., a polypeptide having the amino acid sequence of any one of SEQ ID NOs: 13 and 50-56) may be used, alone or in combination with one or more supportive therapies or active agents, to treat, prevent, or reduce the progression rate and / or severity of an interstitial lung disease (e.g., idiopathic pulmonary fibrosis). In some embodiments, the interstitial lung disease is pulmonary fibrosis. In some embodiments, the interstitial lung disease is caused by any one of the following: silicosis, asbestosis, berylliosis, hypersensitivity pneumonitis, drug use (e.g., antibiotics, chemotherapeutic drags, antiarrhythmic agents, statins), systemic sclerosis, polymyositis, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, an infection (e.g., atypical pneumonia, pneumocystis pneumonia, tuberculosis, chlamydia trachomatis, and / or respiratory syncytial virus), lymphangitic carcinomatosis, cigarette smoking, or developmental disorders. In some embodiments, the interstitial lung disease is idiopathic (e.g., sarcoidosis, idiopathic pulmonary fibrosis, Hamman-Rich syndrome, and / or antisynthetase syndrome). In particular embodiments, the interstitial lung disease is idiopathic pulmonary' fibrosis. In some embodiments, the treatment for idiopathic pulmonary' fibrosis is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of: pirfenidone, N-acetylcysteine, prednisone, azathioprine, nintedanib, derivatives thereof and combinations thereof. In some embodiments, any of the polypeptides disclosed herein (e.g., a polypeptide having the amino acid sequence of any one of SEQ ID NOs: 13 and 50-56) may' be used, alone or in combination with one or more supportive therapies or active agents, to treat, prevent, or reduce the progression rate and / or severity of a kidney-associated disease or condition. As used herein, "kidney-associated disease or condition" can refer to any' disease, disorder, or condition that affects the kidneys or the renal system. Examples of kidney-associated diseases or conditions include, but are not limited to, chronic kidney diseases (or failure), acute kidney diseases (or failure), primary kidney diseases, non-diabetic kidney diseases, glomerulonephritis, interstitial nephritis, diabetic kidney diseases, diabetic nephropathy, glomerulosclerosis, rapid progressive glomerulonephritis, renal fibrosis, Alport syndrome, IDDM nephritis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, renal interstitial fibrosis, focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, pauci-immune rapid progressive glomerulonephritis, IgA nephropathy, polycystic kidney' disease, Dent's disease, nephrocytinosis, Heymann nephritis, autosomal dominant -54- 2024205045   24 Jul 2024 (adult) polycystic kidney disease, autosomal recessive (childhood) polycystic kidney disease, acute kidney injury, nephrotic syndrome, renal ischemia, podocyte diseases or disorders, proteinuria, glomerular diseases, membranous glomerulonephritis, focal segmental glomerulonephritis, pre-eclanipsia, eclampsia, kidney lesions, collagen vascular diseases, benign orthostatic (postural) proteinuria, IgM nephropathy, membranous nephropathy, sarcoidosis, diabetes mellitus, kidney damage due to drugs, Fabry's disease, aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, Sickle cell disease, hemoglobinuria, myoglobinuria, Wegener's Granulomatosis, Glycogen Storage Disease Type 1, chronic kidney disease, chronic renal failure, low Glomerular Filtration Rate (GFR), nephroangiosclerosis, lupus nephritis, ANCA-positive pauci-immune crescentic glomerulonephritis, chronic allograft nephropathy, nephrotoxicity, renal toxicity, kidneynecrosis, kidney damage, glomerular and tubular injury, kidney dysfunction, nephritic syndrome, acute renal failure, chronic renal failure, proximal tubal dy sfunction, acute kidney transplant rejection, chronic kidney transplant rejection, non-IgA mesangioproliferative glomerulonephritis, postinfectious glomerulonephritis, vasculitides with renal involvement of any kind, any hereditary renal disease, any interstitial nephritis, renal transplant failure, kidney cancer, kidney disease associated with other conditions (e.g., hypertension, diabetes, and autoimmune disease), Dent's disease, nephrocytinosis, Heymann nephritis, a primarykidney disease, a collapsing glomerulopathy, a dense deposit disease, a cryoglobulinemia-associated glomerulonephritis, an Henoch-Schonlein disease, a postinfectious glomerulonephritis, a bacterial endocarditis, a microscopic polyangitis, a Churg-Strauss syndrome, an anti-GBM-antibody mediated glomerulonephritis, amyloidosis, a monoclonal immunoglobulin deposition disease, a fibrillary- glomerulonephritis, an immunotactoid glomerulopathy, ischemic tubular injury, a medication-induced tubulo-interstitial nephritis, a toxic tubulo-interstitial nephritis, an infectious tubulo-interstitial nephritis, abacterial pyelonephritis, a viral infectious tubulo-interstitial nephritis which results from a polyomavirus infection or an HIV infection, a metabolic-induced tubulo-interstitial disease, a mixed connective disease, a cast nephropathy, a crystal nephropathy which may results from urate or oxalate or drug-induced crystal deposition, an acute cellular tubulo-interstitial allograft rejection, a tumoral infiltrative disease which results from a lymphoma or a posttransplant lymphoproliferative disease, an obstructive disease of the kidney, vascular disease, a thrombotic microangiopathy, a nephroangiosclerosis, an atheroembolic disease, a mixed connective tissue disease, a polyarteritis nodosa, a calcineurin-inhibitor induced-vascular disease, an acute cellular vascular allograft rejection, an acute humoral allograft rejection, -55- 2024205045   24 Jul 2024 early renal function decline (ERFD), end stage renal disease (ESRD), renal vein thrombosis, acute tubular necrosis, acute interstitial nephritis, established chronic kidney disease, renal artery' stenosis, ischemic nephropathy, uremia, drug and toxin-induced chronic tubulointerstitial nephritis, reflux nephropathy, kidney stones, Goodpasture's syndrome, normocytic normochromic anemia, renal anemia, diabetic chronic kidney disease, IgG4-related disease, von Hippel-Lindau syndrome, tuberous sclerosis, nephronophthisis, medullary’ cystic kidney disease, renal cell carcinoma, adenocarcinoma, nephroblastoma, lymphoma, leukemia, hyposialylation disorder, chronic cyclosporine nephropathy, renal reperfusion injury, renal dysplasia, azotemia, bilateral arterial occlusion, acute uric acid nephropathy, hypovolemia, acute bilateral obstructive uropathy, hypercalcemic nephropathy, hemolytic uremic syndrome, acute urinary retention, malignant nephrosclerosis, postpartum glomerulosclerosis, scleroderma, non-Goodpasture's anti-GBM disease, microscopic polyarteritis nodosa, allergic granulomatosis, acute radiation nephritis, post-streptococcal glomerulonephritis, Waldenstrom's macroglobulinemia, analgesic nephropathy, arteriovenous fistula, arteriovenous graft, dialysis, ectopic kidney, medullary’ sponge kidney, renal osteodystrophy, solitary' kidney, hydronephrosis, microalbuminuria, uremia, haematuria, hyperlipidemia, hypoalbuminaemia, lipiduria, acidosis, hyperkalemia, and edema. In some embodiments, any of the polypeptides disclosed herein (e.g., a polypeptide having the amino acid sequence of any one of SEQ ID NOs: 13 and 50-56) may be used, alone or in combination with one or more supportive therapies or active agents, to treat, prevent, or reduce the progression rate and / or severity’ of chronic kidney disease (e.g., tissue damage, inflammation, and / or fibrosis). Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function may include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with CKD. This disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia, or pericarditis. Recent professional guidelines classify the severity of CKD in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is often called endstage kidney disease, end-stage renal disease, or end-stage kidney' failure, and is largely’ synonymous with the now outdated terms chronic renal failure or chronic kidney failure; and usually' means the patient requires renal replacement therapy, which may involve a form of -56- 2024205045   24 Jul 2024 dialysis, but ideally constitutes a kidney transplant. CKD is initially without specific symptoms and is generally only detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases, various symptoms may manifest as described below. Blood pressure may be increased due to fluid overload and production of vasoacti ve hormones created by the kidney via the renin-angiotensin system, increasing one's risk of developing hypertension and / or suffering from congestive heart failure. Urea may accumulate, leading to azotemia and ultimately uremia (symptoms ranging from, lethargy to pericarditis and encephalopathy). Due to its high systemic circulation, urea is excreted in eccrine sweat at high concentrations and crystallizes on skin as the sweat evaporates ("uremic frost"). Potassium, may accumulate in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20-25 ml / min / 1.73 m2, at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia in CKD can be exacerbated by acidemia (which leads to extracel lul ar shift of potassium) and from lack of insulin. Erythropoietin synthesis may be decreased causing anemia. Fluid volume overload symptoms may occur, ranging from mild edema to life-threatening pulmonary edema. Hyperphosphatemia, due to reduced phosphate excretion, may occur generally following the decrease in glomerular filtration. Hyperphosphatemia is associated with increased cardiovascular risk, being a direct stimulus to vascular calcification. Hypocalcemia may manifest, which is generally caused by stimulation of fibroblast growth factor-23. Osteocytes are responsible for the increased producti on of FGF23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D3). Later, this progresses to secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification that further impairs cardiac function. Metabolic acidosis (due to accumulation of sulfates, phosphates, uric acid etc.) may occur and cause altered enzyme activity by excess acid acting on enzymes; and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia). Acidosis is also due to decreased capacity to generate enough ammonia from the cells of the proximal tubule. Iron deficiency anemia, which increases in prevalence as kidney function decreases, is especially prevalent in those requiring haemodialysis. It is multifactoral in cause, but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression. People with CKD suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with CKD and cardiovascular disease tend to -57- 2024205045   24 Jul 2024 have significantly worse prognoses than those suffering only from the latter. In some embodiments, the chronic kidney disease is a chronic kidney disease mineral bone disorder, a broad syndrome of interrelated skeletal, cardiovascular, and mineral-metabolic disorders arising from kidney disease. CKD-MBD encompasses various skeletal pathologies often referred to as renal osteodystrophy (ROD), which is a preferred embodiment for treatment with any of the polypeptides disclosed herein, or combinations with one or more s upportive therapies or acti ve agents. Depending on the relative contribution of different pathogenic factors, ROD is manifested as diverse pathologic patterns of bone remodeling (Hruska et al., 2008, Chronic kidney disease mineral bone disorder (CKD-MBD); in Rosen et al. (ed) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th ed. American Society for Bone and Mineral Research, Washington D.C., pp 343-349). At one end of the spectrum is ROD with uremic osteodystrophy and low' bone turnover, characterized by a low' number of active remodeling sites, profoundly suppressed bone formation, and low bone resorption. At the other extreme is ROD with hyperparathyroidism, high bone turnover, and osteitis fibrosa. In certain aspects, any of the polypeptides {e.g., a polypeptide having the amino acid sequence of SEQ ID NOs: 13 and 50-56) disclosed herein may be used, alone or in combination with one or more supportive therapies or active agents, to treat, prevent, or reduce the progression rate and / or severity of myelofibrosis (e.g., primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis). In particular, ActRUB antagonists may be used, alone or in combination with one or more supportive therapies or active agents, to treat, prevent, or reduce the progression rate and / or severity of one or more complications of myelofibrosis including, for example, ineffective hematopoiesis, anemia, inflammation, fibrosis (e.g., bone marrow fibrosis, spleen fibrosis, and liver fibrosis), pancytopenia, thrombocytopenia, extramedullary hematopoiesis (e.g., splenic extramedullary hematopoiesis, hepatic extramedullary' hematopoiesis, pulmonary' extramedullary hematopoiesis, and lymphatic extramedullary hematopoiesis), hepatomegaly, splenomegaly, osteosclerosis, osteomyelofibrosis, poikilocytosis, fatigue, weight loss, night sweats, fever, pruritus, bone pain, early satiety, abdominal pain or discomfort, arthralgias, myalgias, parasthesias, cachexia, splenic infarct, and bleeding. As used herein, inhibition of tire fibrotic response of a ceil, includes, but is not limited to the inhibition of the fibrotic response of one or more cells within the liver (or liver tissue); one or more cells within the kidney (or renal tissue); one or more cells within muscle tissue; one or more cells within the heart (or cardiac tissue); one or more cells wdthin the pancreas; -58- 2024205045   24 Jul 2024 one or more cells within the skin; one or more ceils within the bone, one or more cells within the vasculature, one or more stem cells, or one or more cells within the eye. In some embodiments, any of the 1II polypeptides of the disclosure may be used for treating an autoimmune disease or disorder. In some embodiments, the autoimmune disease or disorder is selected from the group consisting of: spondyloarthropathies; ankylosing spondylitis, arthritis, psoriatic arthritis / spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, undifferentiated spondyloarthropathies; reactive arthritis, rheumatism, inflammatory bowel syndrome, Crohns Disease, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome. In some embodiments, any of the TpRII polypeptides of the disclosure may be used for treating a metabolic disorder. In some embodiments, the metabolic disorder is obesity or diabetes (e.g., Type I or Type II diabetes), fatty liver disease, diabetic neuropathy, peripheral neuropathy, diabetic retinopathy, diabetic ulcerations, retinopathy ulcerations, diabetic m aero vasculopathy. In some embodiments, any of the TpRII polypeptides of the disclosure may be used for treating an infectious disease or following an organ or tissue transplantation. In some embodiments, any of the TpRII polypeptides of the disclosure may be used for treating chronic obstructive pulmonary disease (COPD), chronic obstructive airway disorder, idiopathic pulmonary fibrosis and / or asthma. In part, the disclosure also relates to methods of treating pulmonary hypertension (e.g., pulmonary' arterial hypertension) comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide (e.g., a polypeptide comprising the amino acid sequence of any' one of SEQ ID NOs: 13 and 50-56). In some embodiments, the disclosure contemplates methods of treating one or more complications of pulmonary' hypertension (e.g,, smooth muscle and / or endothelial cell proliferation in the pulmonary artery', angiogenesis in the pulmonary artery, dyspnea, chest pain, pulmonary vascular remodeling, right ventricular hypertrophy , and pulmonary' fibrosis) comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. In some embodiments, the disclosure contemplates methods of preventing one or more complications of pulmonary' hypertension comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. In some embodiments, the disclosure contemplates methods of reducing the progression rate of pulmonary' hypertension comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. In some embodiments, the disclosure contemplates methods -59- 2024205045   24 Jul 2024 of reducing the progression rate of one or more complications of pulmonary hypertension comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. In some embodiments, the disclosure contemplates methods of reducing the severity of pulmonary' hypertension comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. In some embodiments, the disclosure contemplates methods of reducing the severity of one or more complications of pulmonary hypertension comprising administering to a patient in need thereof an effective amount of a TpRII polypeptide. Optionally, methods disclosed herein for treating, preventing, or reducing the progression rate and / or severity of pulmonary hypertension, particularly treating, preventing, or reducing the progressi on rate and / or severity of one or more complications of pulmonary hypertension, may further comprise administering to the patient one or more supportive therapies or additional active agents for treating pulmonary' hypertension. Ilie present invention contemplates the use of TpRII polypeptides in combination with one or more other therapeutic modalities. Thus, in addition to the use of TpRII polypeptides, one may also administer to the subject one or more "standard" therapies for treating fibrotic disorders. For example, the TpRII polypeptides can be administered in combination with (i.e., together with) cytotoxins, immunosuppressive agents, radiotoxic agents, and / or therapeutic antibodies. Particular co-therapeutics contemplated by the present invention include, but are not limited to, steroids (e.g., corticosteroids, such as Prednisone), immune-suppressing and / or anti-inflammatory agents (e.g., gamma-interferon, cyclophosphamide, azathioprine, methotrexate, penicillamine, cyclosporine, colchicine, antithymocyte globulin, mycophenolate mofetil, and hydroxychloroquine), cytotoxic drugs, calcium channel blockers (e.g., nifedipine), angiotensin converting enzyme inhibitors (ACE) inhibitors, para-aminobenzoic acid (PABA), dimethyl sulfoxide, transforming growth factor beta (TGFP) inhibitors, interleukin-5 (IL-5) inhibitors, and pan caspase inhibitors. Additional anti-fibrotic agents that may be used in combination with TBRH polypeptides include, but are not limited to, lectins (as described in, for example, U.S. Patent No.: 7,026,283, the entire contents of which is incorporated herein by reference), as well as the anti-fibrotic agents described by Wynn et al (2007, J Clin Invest 117:524-529, the entire contents of which is incorporated herein by reference). For example, additional anti-fibrotic agents and therapies include, but are not limited to, various anti-inflammatory. / immunosuppressive / cytotoxic drags (including colchicine, azathioprine, cyclophosphamide, prednisone, thalidomide, pentoxifylline and theophylline), TGFp signaling modifiers (including relaxin, SAIAD7. HGF, and BMP7, as well as TGFpl, TpRI, TpRII, EGR-I, and -60- 2024205045   24 Jul 2024 CTGF inhibitors), cytokine and cytokine receptor antagonists (inhibitors of IL-ip, IL-5, IL-6, IL- 13, IL-21, IL-4R, IL-13Ral, GM-CSF, TNF-a, oncostatin M, W1SP-I, and PDGFs), cytokines and chemokincs (IFN-y, IFN-a / p, IL-12, IL-10, HGF, CXCL10, and CXCL11), chemokine antagonists (inhibitors of CXCL1, CXCL2, CXCL12, CCL2, CCL3, CCL6, CCL17, and CCL18), chemokine receptor antagonists (inhibitors of CCR2, CCR3, CCR5, CCR7, CXCR2, and CXCR4), TLR antagonists (inhibitors of TLR3, TLR4, and TLR9), angiogenesis antagonists (VEGF-specific antibodies and adenosine deaminase replacement therapy), antihypertensive drugs (beta blockers and inhibitors of ANG 11, ACE, and aldosterone), vasoactive substances (ET-1 receptor antagonists and bosetan), inhibitors of the enzymes that synthesize and process collagen (inhibitors of prolyl hydroxylase), B cell antagonists (rituximab), integrin / adhesion molecule antagonists (molecules that block al pi and avP6 integrins, as well as inhibitors of integrin-linked kinase, and antibodies specific for 1CAM-1 and VCAM-1), proapoptotic drugs that target myofibroblasts, MMP inhibitors (inhibitors of MMP2, MMP9, and MMPI2), and T1MP inhibitors (antibodies specific for TIMP-1 ). The TpRII polypeptide and the co-therapeutic agent or co-therapy can be administered in the same formulation or separately. In the case of separate administration, the TpRII polypeptide can be administered before, after, or concurrently with the co-therapeutic or co-therapy. One agent may precede or follow administration of the other agent by intervals ranging from minutes to weeks. In embodiments where two or more different kinds of therapeutic agents are applied separately to a subject, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that these different kinds of agents would still be able to exert an advantageously combined effect on the target tissues or cells. 10. Pharmaceutical Compositions Idle therapeutic agents described herein (e.g., TpRII fusion polypeptides) may be formulated into pharmaceutical compositions. Pharmaceutical compositions for use in accordance with the present disclosure may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Such formulations will generally be substantially pyrogen-free, in compliance with most regulatory requirements. In certain embodiments, the therapeutic method of the disclosure includes administering the composition systemically, or locally as an implant or device. When administered, the therapeutic composition for use in this disclosure is in a pyrogen-free, -61- 2024205045   24 Jul 2024 physiologically acceptable form. Therapeutically useful agents other than the TpRII signaling antagonists which may also optionally be included in the composition as described above, may be administered simultaneously or sequentially with the subject compounds (e.g., TpRII polypeptides) in the methods disclosed herein. 5           Typically, protein therapeutic agents disclosed herein will be administered parentally, and particularly intravenously or subcutaneously. Pharmaceutical compositions suitable for parenteral administration may comprise one or more TpRII polypeptides in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into 10 sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene 15 glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Hie compositions and formulations may, if desired, be presented in a pack or 20 dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration Further, the composition may be encapsulated or injected in a form for delivery to a target tissue site. In certain embodiments, compositions of the present invention may include 25 a matrix capable of delivering one or more therapeutic compounds (e.g., TpRII polypeptides) to a target tissue site, providing a structure for the developing tissue and optimally capable of being resorbed into the body. For example, the matrix may provide slow release of the TpRII polypeptides. Such matrices may be formed of materials presently in use for other implanted medical applications. 30          The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the subject compositions will define the appropriate formulation. Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid and polyanhydrides. Other potential 2024205045   24 Jul 2024 materials are biodegradable and biologically well defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are non-biodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of 5   combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. In certain embodiments, methods of the invention can be administered for orally, e.g., 10 in the form of capsules, cachets, pil ls, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of an 15 agent as an active ingredient. An agent may also be administered as a bolus, electuary' or paste. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), one or more therapeutic compounds of the present invention may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate 20 or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution 25 retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the 30 pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. 2024205045   24 Jul 2024 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert, diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. The compositions of the invention may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacteri al and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. It is understood that the dosage regimen will be determined by the attending physician considering various factors which modify the action of the subject compounds of the invention (e.g., TflRH fusion polypeptides). The various factors include, but are not limited to, the patient's age, sex, and diet, the severity disease, time of administration, and other clinical factors. Optionally, the dosage may vary with the type of matrix used in the reconstitution and the types of compounds in the composition. The addition of other known growth factors to the final composition, may also affect the dosage. Progress can be monitored by periodic assessment of bone growth and / or repair, for example, X-rays (including DEXA), histomorphometric determinations, and tetracycline labeling. In certain embodiments, the present invention also provides gene therapy for the in vivo production of T^RII fusion polypeptides. Such therapy would achieve its therapeutic effect by introduction of the TpRII polynucleotide sequences into cells or tissues having the -64- 2024205045   24 Jul 2024 disorders as listed above. Delivery' of TpRII polynucleotide sequences can be achieved using a recombinant expression vector such as a chimeric virus or a colloidal dispersion system. Preferred for therapeutic delivery' of TpRII polynucleotide sequences is the use of targeted liposomes. 5           Various viral vectors which can be utilized for gene therapy as taught herein include adenovirus, herpes virus, vaccinia, or, preferably, an RNA virus such as a retrovirus. Preferably, the retroviral vector is a derivative of a murine or avian retrovirus. Examples of retroviral vectors in which a single foreign gene can be inserted include, but are not limited to: Moloney murine leukemia vims (MoMuLV), Harvey murine sarcoma virus (HaMuSV), 10 murine mammary tumor virus (MuMTV), and Rous Sarcoma Virus (RSV). A number of additional retroviral vectors can incorporate multiple genes. All of these vectors can transfer or incorporate a gene for a selectable marker so that transduced cells can be identified and generated. Retroviral vectors can be made target-specific by attaching, for example, a sugar, a glycolipid, or a protein. Preferred targeting is accomplished by using an antibody. Those 15   of skill in the art will recognize that specific polynucleotide sequences can be inserted into the retroviral genome or attached to a viral envelope to allow target specific delivery of the retroviral vector containing the TpRII polynucleotide. In a preferred embodiment, the vector is targeted to bone or cartilage. Alternatively, tissue culture cells can be directly transfected with plasmids encoding 20 the retroviral structural genes gag, pol and env, by conventional calcium phosphate transfection. These cells are then transfected with the vector plasmid containing the genes of interest. The resulting cells release the retroviral vector into the culture medium. Another targeted delivery' system for TpRII polynucleotides is a colloidal dispersion system. Colloidal dispersion systems include macromolecule complexes, nanocapsules, 25 microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. The preferred colloidal system of this invention is a liposome. Liposomes are artificial membrane vesicles which are useful as delivery vehicles in vitro and in vivo. RNA, DNA and intact virions can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form (see e.g., Fraley, et al., Trends 30 Biochem. Sci., 6:77, 1981). Methods for efficient gene transfer using a liposome vehicle, are known in the art, see e.g., Mannino, et al., Biotechniques, 6:682, 1988. Hie composition of the liposome is usually a combination of phospholipids, usually in combination w'ith steroids, especially cholesterol. Other phospholipids or other lipids may also be used. The physical 2024205045   24 Jul 2024 characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations. Examples of lipids useful in liposome production include phosphatidyl compounds, such as phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, 5 phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides. Illustrative phospholipids include egg phosphatidylcholine, dipalmitoylphosphatidylcholine, and di stearoylphosphatidyIcholine. The targeting of liposomes is also possible based on, for example, organ-specificity, cell-specificity, and organelle-specificity and is known in the art. The disclosure provides formulations that may be varied to include acids and bases to 10 adjust the pH; and buffering agents to keep the pH within a narrow range. EXEMPLIFICATION Ilie invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of 15 certain embodiments of the present invention, and are not intended to limit the invention. Example 1. Generation of receptor fusion protein variants TpRII ECD vanants TpRII fusion proteins comprising a soluble extracellular portion of human TpRII and 20 a humanFc portion were generated. For each fusion protein, a TpRII amino acid sequence having the amino acid sequence of SEQ ID NO: 18 was fused to an IgG Fc portion having the amino acid sequence of SEQ ID NO: 20 by means of one of several different linkers. Each of the fusion proteins also included a TPA leader sequence having the amino acid sequence of SEQ ID NO: 23 (below). 25         Tissue plasminogen activator (TPA): MDAMKRGLCCVLLLCGAVFVSP (SEQ ID NO: 23) An illustration summary of several of the constructs designed is provided as Figure 3. A table detailing the sequences for the different constructs tested in the Exemplification section is provided below': Construct Name Construct Amino Acid Sequence Linker Sequence hTPRII-hFc SEQ ID NO: 9 TGGG (SEQ ID NO: 3) hTpRIl (G4S)2-hFc SEQ ID NO: 15 TGGGGSGGGGS (SEQ ID NO: 4) 2024205045   24 Jul 2024 hTpRII (G4S)3-hFc SEQ ID NO: 11 TGGGGSGGGGSGGGGS (SEQ ID NO: 5) hTpRII (G4S)4-hFc SEQ ID NO: 13 TGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 6) hTpRII extended hinge-hFc SEQ ID NO: 17 TGGGPKSCDK (SEQ ID NO: 7) hTpRII (G4S)5-hFc SEQ ID NO: 44 TGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 25)                               ’ hTpRII (G4S)6-hFc SEQ ID NO: 45 TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 26) The amino acid sequences for the construct components and each of the constructs, along with the nucleic acid sequence used to express these constructs, are provided below. 5          TpRIIPortion: Amino Acid Sequence 10 TIPPHVQKSD PQLCKFCDVR ETVCHDPKLP IFSEEYNTSN VEMEAQKDEI FSTCDNQKSC YHDFILEDAA PD (SEQ ID ICPSCNRTAH MSNCSITSIC SPKCIMKEKK NO: 18) PLRHINNDM1 EKPQEVC5ZA.V KPGETFFMCS VTDNNGAVKF WRKNDENITL CSSDECNDNI 15 Fc Portion: Amino Acid Sequence 1    THTCPPCPAP ELLGGPSVFL 51   VKFNWYVDGV EVHNAKTKPR 101  VSNKALPAPI EKTISKAKGQ 151  YPSDIAVEWE SNGQPENNYK 201  FSCSVMHEAL HNHYTQKSLS FPPKPKDTLM EEQYNSTYRV PREPQVYTLP TTPPVLDSDG ISRTPEVTCV VSVLTVLHQD P S RE EMT KN Q SFFLYSKLTV WD'ZSHEDPE WLNGKEYKCK VSLTCLVKGF DKSRWQQGNV LSPGK (SEQ ID NO: 20) hTpRII-hFc: Nucleic Acid Sequence 20 25 30 35 40 1 51 101 151 201 251 301 351 4 01 4 51 501 551 601 651 7 01 751 8 01 851 901 951 1001 ATGGATGCAA AGTCTTCGTT ATGTGGAAAT AGGACTGCCC CAACAACGGT gattttccac ZUCTCCATCT GAATGACGAG CCTACC1A.TGA AAG GAA AAAA TGATGAGTGC ATCCTGACAC GAACTCCTGG CACCCTCATG T GA.G u CAC GA. GAGGTGCATA GTACCGTGTG GCAAGGAGTA GAGAAAACCA CAC C T c C C CCTGCCTGGT TGAAGAGAGG TCGCCCGGCG GGAGGCCCAG ATCCACTGAG GCAGTCAAGT CTGTGACAAC GTGAGAAGCC AACZ.TAACAC CTTTATTCTG AAAAGCCTGG AATGACAACA CGGTGGTGGA GGGGACCGTC AT C. T C C C G GA AGACCCTGAG ATGCC1AA.GAC GTCAGCGTCC CAAGTGCAAG TCTCCAAAGC CCATCCCGGG CAAAGGCTTC GCTCTGCTGT CCACGZlTCCC AAAGATGAAA ACATATTAAT TTCCACAACT CAGAAATCCT ACAGGAAGTC TAGAGACAGT GAAGATGCTG TGAGACTTTC TCATCTTCTC ACTCACACAT AGTCTTCCTC CCCCTGAGGT GTCZAGTTCA AZAGCCGCGG TCACCGTCCT GTCTCCAACA CAAAGGGCAG AGGAGATGAC TATCCCAGCG GTGCTGCTGC ZlCCGCACGTT TCATCTGCCC AACGACATGA GTGTAAATTT G CAT GAG CAA TGTGTGGCTG TTGCCATGAC CTTCTCCAAA TTCATGTGTT AGAAGAATAT G C C CAC C GT G TTCCCCCCAA CACAT G C GT G ACTGGT / ACGT GAGGAGCAGT GCACCAGGAC AA G C C C T C C C AG C C C C CAT C CCCCGAGAAC CACAGGTGTA CAAGAYC CAG GT CAGC CT GA ACAT C GC C GT GGAG T GGGAG TGTGTGGAGC CAGAAGTCGG CAGCTGTAAT TAGTCACTGA TGTGATGTGA CTGCAGCATC TATGGAGAAA CCCAAGCTCC GTGCATTATG CCTGTAGCTC AACACl.Agc / 1 CCCAGCACCT AAC C CAAG GA GTGGTGGACG 2024205045   24 Jul 2024 1051 AGCAATGGGC AGCCGGAGAA CAACTACAAG ACCACGCCTC CCGTGCTGGA 1101   CTCCGACGGC TCCTTCTTCC TCTATAGCAA GCTCACCGTG GACAAGAGCA 1151   GGTGGCAGCA GGGGAACGTC TTCTCATGCT CCGTGATGCA TGAGGCTCTG 1201 CACAACCACT ACACGCAGAA GAGCCTCTCC CTGTCTCCGG GTAAATGA (SEQ ID NO: 8) 10 15 hT^RII-hFc: Amino Acid Sequence 1 MDAMKRGLCC VLLLCGAVFV SPGATIPPHV QKSDVEMEAQ KDEIICPSCN 51   RTAHPLRHIN NDMIVTDNNG AVKFPQLCKF CDVRFSTCDN QKSCMSNCSI 101   TSICEKPQEV CVAVWRKNDE NITLETVCHD PKLPYHDFIL EDAASPKCIM 151 KEKKKPGETF FMCSCSSDEC NDNIIFSEEY NTSNPDTGGG THTCPPCPAP 201 ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV WDVSHEDPE VKFNWYVDGV 251 EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI 301 EKTISKAKGQ PREPQVYTLP PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE 351 SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL 401 HNHYTQKSLS LSPGK (SEQ ID NO: 9) 20 25 30 35 40 45 hTfiRII (G4S)3-hFc: Nucleic Acid Sequence 1 51 ATGGATGCAA AGTCTTCGTT TGAAGAGAGG TCGCCCGGCG GCTCTGCTGT CCACGA.TCCC 101 ATGTGGAAAT GGAGGCCCAG AAAGATGAAA 151 AGGACTGCCC ATCCACTGAG ACATATTAAT 201 CAACAACGGT GCAGTCAAGT TTCCACAAxCT 251 GATTTTCCAC CTGTGACAAC CAGAAATCCT 301 ACCTCCATCT GTGAGAAGCC A.CAGGAA.GTC 351 GAATGACGAG AACATAA.CAC TAGAGACAGT 4 01 CCTA.CCATGA CTTTATTCTG GAA.GATGCTG 451 AAGGAAAAAA. AAAAGCCTGG TGA.GACTTTC 501 TGATGAGTGC AAT GAC1AAC A TCA.TCTTCTC 551 ATCCTGACAC CGGTGGTGGA GGAAGTGGTG 601 GGAAGTACTC ACACATGCCC ACCGTGCCCA 651 ACCGTCAGTC TTCCTCTTCC CCCCAAAACC 701 CCCGGACCCC TGAGGTCACA TGCGTGGTGG 751 CCTGAGGTCA AGTTCAACTG GTACGTGGAC 8 01 CAAGACAAAG CCGCGGGAGG AGCAGTACAA 8 51 GCGTCCTCAC CGTCCTGCAC CAGGACTGGC 9 01 TGCAAGGTCT CC1AACAAAGC CCTCCCAGCC 951 CAAAGCC.AAA GGGCAGCCCC GAGAACCACA 1001 CCCGGGAGGA GATGACCAAG AACCAGGTCA 1051 ggcttctatc CCAGCGACAT CGCCGTGGAG 1101 GGAGAACAAC TACAAGACCA CGCCTCCCGT 1151 TCTTCCTCTA TAGCAAGCTC ACCGTGGACA 12 01 AACGTCTTCT CATGCTCCGT GATGCATGAG 12 51 GCAGAAGAGC CTCTCCCTGT CTCCGGGTAA GTGCTGCTGC ACCGCACGTT TCATCTGCCC AACGACATGA GTGTAAATTT GCATGAGCAA TGTGTGGCTG TTGCCA.TGAC CTTCTCCAAA TTCATGTGTT AGAAGA-ATAT GAGGTGGTTC GCACCTGAAC CAAGGACACC TGGACGTGAG GGCGTGGAGG CAGCACGTAC TGAATGGCAA CCCATCGAGA GGTGTACACC GCCTGACCTG TGGGAGAGCA GCTGGACTCC AGAGCAGGTG GCTCTGCACA ATGA (SEQ : TGTGTGGAGC CAGAAGTCGG CAGCTGTAAT TAGTCACTGA TGTGATGTGA CTGCAGCATC TAT G GAG AAA CCCAAGCTCC GTGC.ATTATG CCTGTAGCTC AACACCAGCA TGGAGGTGGT TCCTGGGGGG CTCATGATCT CCACGAAGAC TGCATAATGC CGTGTGGTCA GGAGTACAAG AAACCATCTC CTGCCCCCAT CCTGGTCAAA ATGGGCAGCC GACGGCTCCT GCAGCAGGGG ACCACTACAC :D NO: 10) 50 hTpRIl (G4S)3-hFc: Amino Acid Sequence 1   MDAMKRGLCC VLLLCGAVFV SPGATIPPHV QKSDVEMEAQ KDEIICPSCN 51   RTAHPLRHIN NDMIVTDNNG AVKFPQLCKF CDVRFSTCDN QKSCMSNCSI 101   TSICEKPQEV CVAVWRKNDE NITLETVCHD PKLPYHDFIL EDAASPKCIM 151   KEKKKPGETF FMCSCSSDEC NDNIIFSEEY NTSNPDTGGG GSGGGGSGGG 201   GSTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED 251   PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK 301   CKVSNKALPA. PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK 2024205045   24 Jul 2024 10 15 20 25 35 40 45 50 GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID NO: 11) hTpRII (G4S)4-hFc: Nucleic Acid Sequence 1   ATGGATGCAA TGAAGAGAGG GCTCTGCTGT 51   AGTCTTCGTT TCGCCCGGCG CCACGATCCC 101   ATGTGGAAAT GGAGGCCCAG AAAGATGAAA 151   AGGACTGCCC ATCCACTGAG ACATATTAAT 201   CAACAACGGT GCAGTCAAGT TTCCACAACT 251   GATTTTCCAC CTGTGACAAC CAGAAATCCT 301   ACCTCC1ATCT GTGAGAAGCC ACAGGAAGTC 351   GAATGACGAG AACATAACAC TAGAGACAGT 401   CCTACCATGA CTTTATTCTG GAAGATGCTG 451   AAGGAAAAAA AAAAGCCTGG TGAGACTTTC 501   TGATGAGTGC AATGACAACA TCATCTTCTC 551   ATCCTGACAC CGGTGGTGGA GGTTCTGGAG 601   GGTTCTGGAG GTGGTGGAAG TACTCACACA 651   TGAACTCCTG GGGGGACCGT CAGTCTTCCT 701   ACACCCTCAT GATCTCCCGG ACCCCTGAGG 751   GTGA.GCCACG AAGACCCTGA GGTCAAGTTC 801   GGAGGTGCAT AATGCCAAGA CAAAGCCGCG 851   CGTACCGTGT GGTCAGCGTC CTCACCGTCC 901   GGCAAGGAGT ACAAGTGCAA GGTCTCCAAC 951   CGAGAAAACC ATCTCCAAAG CCAAAGGGCA 1001   ACACCCTGCC CCCATCCCGG GAGGAGATGA 1051   ACCTGCCTGG TCAAAGGCTT CTATCCCAGC 1101   GAGCAATGGG CAGCCGGAGA. ACAACTACAA 1151   ACTCCGACGG CTCCTTCTTC CTCTATAGCA 1201   AGGTGGCAGC AGGGGAACGT CTTCTCATGC 1251   GCACAACCAC TACACGCAGA AGAGCCTCTC (SEQ ID NO: 12) hTpRII (G4S)4-hFc: Amino Acid Sequence 1 51 101 151 2 01 251 301 351 401 MDAMKRGLCC RTAHPLRHIN TSICEKPQEV KEKKKPGETF GSGGGGSTHT VSHEDPEVKF GKEYKCKVSN TCLVKGFYPS RWQQGNVFSC VLLLCGAVFV NDMIVTDNNG CVA.VWRKNDE FMCSCSSDEC CPPCPAJ9ELL NWYVDGVEVH KALPAPIEKT DIAVEWESNG S P GATIP P H V AVKFPQLCKF NITLETVCHD NDNIIFSEEY GGPSVFLFPP NAKTKPREEQ ISKAKGQPRE QPENNYKTTP YTQKSLSLSP TGTGTGGAGC CAGAAGTCGG CAGCTGTAAT TAGTCACTGA TGTGAT GTGA CTGCAGCATC TATGGAGAAA CCCAA.GCTCC GTGCATTATG CCTGTAxGCTC AACAC CAG C A T GGT GGAGGT GCCCAGCACC AAACCCAAGG GGTGGTGGA.C TGGACGGCGT TACAACAGCA. CTGGCTGAAT CAGCCCCCAT CCACAGGTGT GGTCAGCCTG TGGAGTGGGA CCCGTGCTGG GGAC1AAGAGC ATGAGGCTCT GGTAAATGA QKSDVEMEAQ KDEIICPSCN C D VR FS T C D N QKS CMSNC SI PKLPYHDFIL EDAASPKCIM NTSNPDTGGG GSGGGGSGGG KPKDTLMISR YNSTYRVVSV PQVYTLPPSR PVLDSDGSFF GK (SEQ ID TPEVTCVWD LTVLHQDWLN E EMT KN Q VS L LYSKLTVDKS NO: 13) hT^RII (G4S)4-hFc: Amino Acid Sequence lacking leader sequence 1   GATIPPHVQK SDVEMEAQKD EIICPSCNRT AHPLRHINND MIVTDNNGAV 51   KFPQLCKFCD VRFSTCDNQK SCMSNCSITS ICEKPQEVCV AVWRKNDENI 101   TLETVCHDPK LPYHDFILED AASPKCIMKE KKKPGETFFM CSCSSDECND 151   NIIFSEEYNT SNPDTGGGGS GGGGSGGGGS GGGGSTHTCP PCPAPELLGG 201   PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA 251   KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS 301   KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP 351   ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT 401 QKSLSLSPGK (SEQ ID NO: 50) 2024205045   24 Jul 2024 10 hT^RII (G4S)4-hFc: A mino Acid Sequence lacking leader sequence and lacking glycine prior to hTftRII portion 1   ATIPPHVQKS DVEMEAQKDE IICPSCNRTA HPLRHINNDM IVTDNNGAVK 51   FPQLCKFCDV RFSTCDNQKS CMSNCSITSI CEKPQEVCV / R WRKNDENIT 101   LETVCHDPKL PYHDFILEDA ASPKCIMKEK KKPGETFFMC SCSSDECNDN 151   IIFSEEYNTS NPDTGGGGSG GGGSGGGGSG GGGSTHTCPP CPAPELLGGP 201   SVFLFPPKPK DTLMISRTPE VTCVPA / DVSH EDPEVKFNWY VDGVEVHNAK 251   TKPREEQYNS TYRWSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK 301   AKGQPREPQV YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE 351   NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ 401   KSLSLSPGK (SEQ ID NO: 52) hTpRII (G4S)4-hFc: Amino Acid Sequence lacking leader sequence and lacking glycine and alanine prior to hTpRIIportion 1   TIPPHVQKSD VEMEAQKDEI ICPSCNRTAH PLRHINNDMI VTDNNGAVKF 51   PQLCKFCDVR FSTCDNQKSC MSNCSITSIC EKPQEVCVAV WRKNDENITL 101   ETVCHDPKLP YHDFILEDAA SPKCIMKEKK KPGETFFMCS CSSDECNDNI 151   IFSEEYNTSN PDTGGGGSGG GGSGGGGSGG GGSTHTCPPC PAPELLGGPS 2 01   VFLFPPKPKD TLMISRTPEV TCV“WDVSHE DPEVKFNWYV DGVEVHNAKT 251   KPREEQYNST YRWSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA 301   KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN 351   NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK 401 SLSLSPGK (SEQ ID NO: 51) 25 hTpRII (G4S)4-hFc: Ammo Acid Sequence lacking leader sequence and lacking glycine, alanine, and threonine prior to hTpRII portion 30 35 1   IPPHVQKSDV EMEAQKDEII CPSCNRTAHP 51   QLCKFCDVRF STCDNQKSCM SNCSITSICE 101   TVCHDPKLPY HDFILEDAAS PKCIMKEKKK 151   FSEEYNTSNP DTGGGGSGGG GSGGGGSGGG 2 01   FLFPPKPKDT LMISRTPEVT CVWDVSHED 251   PREEQYNSTY RWSVLTVLH QDWLNGKEYK 301   GQPREPQVYT LPPSREEMTK NQVSLTCLVK 351   YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG LRHINNDMIV KPQEVCVAW PGETFFMCSC GSTHTCPPCP PEVKFNWYVD CKVSNKALPA GFYPSDIAVE NVFSCSVMHE TDNNGAVKFP RKNDENITLE SSDECNDNII APELLGGPSV GVEVHNAKTK PIEKTISKAK WE SN GQ P ENN ALHNHYTQKS 401 LSLSPGK (SEQ ID NO: 53) hTpRII (G4S)4-hFc: Amino Acid Sequence lacking leader sequence and lacking glycine, alanine, threonine, and isoleucine prior to hTpRIIportion 40 1   PPHVQKSDVE MEAQKDEIIC 51   LCKFCDVRFS TCDNQKSCMS 101   VCHDPKLPYH DFILEDAASP PSCNRTAHPL NCSITSICEK 45 151   SEEYNTSNPD TGGGGSGGGG 201   LFPPKPKDTL MISRTPEVTC 251   REEQYNSTYR WSVLTVLHQ 301   QPREPQVYTL PPSREEMTKN 351   KTTPPVLDSD GSFFLYSKLT 401   SLSPGK (SEQ ID NO: 54) KCIMKEKKKP SGGGGSGGGG VWDVSHEDP D W L N G K E Y K C QVSLTCLVKG VDKSRWQQGN RH1NNDMIVT PQEVCVAVTVR GETFFMCSCS DNNGAVKFPQ KNDENITLET SDECNDNIIF S T H T C P P C PA P E L L G G P SVF EVKFNWYVDG VEVHNAKTKP KVSNKALPAP FYPSDIAVEW VFSCSVMHEA IEKTISKAKG ESNGQPENNY LHNHYTQKSL 50 hTBRIl (G4S)4-hFc: Amino Acid Sequence lacking leader sequence and lacking glycine, alanine, threonine, isoleucine, and proline prior to hTpRJI portion PHVQKSDVEM EAQKDEIICP SCNRTAHPLR HINNDMIVTD NNGA.VKFPQL 51 CKFCDVRFST CDNQKSCMSN CSITSICEKP QEVCVAVWRK NDENITLETV 2024205045   24 Jul 2024 101 CHDPKLPYHD FILEDAASPK CIMKEKKKPG ETFFMCSCSS DECNDNIIFS 151 EEYNTSNPDT GGGGSGGGGS GGGGSGGGGS THTCPPCPAP ELLGGPSVFL 2 01 FPPKPKDTLM ISRTPEVTCV WDVSHEDPE VKFNWYVDGV EVHNAKTKPR 251 EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ 301   PREPQVYTLP PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK 351   TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS 401 LSPGK (SEQ ID NO: 55) hTpRII (G4S)4-hFc: Amino Acid Sequence lacking leader sequence and lacking 10             glycine, alanine, threonine, isoleucine, proline, and proline prior to hT^RH portion 15 20 1 51 101 151 201 2 51 3 01 351 4 01 HVQKSDVEME KFCDVRFSTC HDPKLPYHDF EYNTSNPDTG PPKPKDTLMI EQYNSTYRW REPQVYTLPP TPPVLDSDGS SPGK (SEQ AQKDEIICPS DNQKSCMSNC ILEDAASPKC GGGSGGGGSG SRTPEVTCW SVLTVLHQDW SREEMTKNQV FFLYSKLTVD ID NO: 56) CNRTAHPLRH SITSICEKPQ IMKEKKKPGE GGGSGGGGST VDVSHEDPEV LNGKEYKCKV SLTCLVKGFY KSRWQQGNVF INNDMIVTDN EVCVAVWRKN TFFMCSCSSD HTCPPCPAPE KFNWYVDGVE SNKALPAPIE PSDIAVEWES SCSWIHEALH NGAVKFPQLC DENITLETVC ECNDNIIFSE LLGGPSVFLF VHNAKTKPRE KTISKAKGQP NGQPENNYKT NHYTQKSLSL 25 30 35 40 45 hTpRII (G4S)2-hFc: Nucleic A cid Sequence 1 ATGGATGCAA TGAAGAGAGG GCTCTGCTGT GTGCTGCTGC TGTGTGGAGC 51 AGTCTTCGTT TCGCCCGGCG CCACGATCCC ACCGCACGTT CAGAAGTCGG 101 ATGTGGAAAT GGAGGCCCAG AAAGATGAAA TCATCTGCCC CAGCTGTAAT 151 AGGACTGCCC ATCCACTGAG ACATATTAAT AACGACATGA TAGTCACTGA 2 01 CAACAACGGT GCAGTCAAGT TTCCACAACT GTGTAAATTT TGTGATGTGA 251 GATTTTCCAC CTGTGACAAC CAGAAATCCT GCATGAGCAA CTGCAGCATC 301 ACCTCCATCT GTGAGAAGCC ACAGGAAGTC TGTGTGGCTG TATGGAGAAA 351 GAATGACGAG AACATAACAC TAGAGACAGT TTGCCATGAC CCCAAGCTCC 401 CCTACCATGA ctttattctg GAAGATGCTG CTTCTCCAAA GTGCATTATG 451 AAGGAAAAAA AAAAGCCTGG TGAGACTTTC TTCATGTGTT CCTGTAGCTC 501 TGATGAGTGC AATGAC1AACA TCATCTTCTO AGAAGAATAT AACACCAGCA 551 ATCCTGACAC CGGTGGAGGT GGTTCTGGAG GTGGTGGAAG TACTCACACA 601 TGCCCACCGT GCCCAGCACC TGAACTCCTG GGGGGACCGT CAGTCTTCCT 651 CTTCCCCCCA 1- CAmG G ACACCCTCAT GATCTCCCGG ACCCCTGAGG 7 01 TCACATGCGT GGTGGTGGAC GTGAGCCACG AAGACCCTGA GGTCAAGTTC 751 AACTGGTACG TGGACGGCGT GGAGGTGCAT AATGCCAAGA CAAAGCCGCG 801 GGAGGAGCAG TACAACAGCA CGTACCGTGT GGTCAGCGTC CTCACCGTCC 851 TGCACCAGGA CTGGCTGAAT GGCAAGGAGT ACAAGTGCAA GGTCTCCAAC 901 AAAGCCCTCC CAGCCCCCAT CGAGAAAACC ATCTCCAAAG CCAAAGGGCA 951 GCCCCGAGAA CCACAGGTGT A.C Av C C T G C C CCCATCCCGG GAGGAGATGA 1001 CCAAGAACCA GGTCAGCCTG ACCTGCCTGG TCAAAGGCTT CTATCCCAGC 1051 GACATCGCCG TGGAGTGGGA GAGCAATGGG CAGCCGGAGA ACAACTACAA 1101 GACCACGCCT CCCGTGCTGG ACTCCGACGG CTCCTTCTTC CTCTATAGCA 1151 AGCTCACCGT GGACAAGAGC AGGTGGCAGC AGGGAAACGT CTTCTCATGC 1201 TCCGTGATGC ATGAGGCTCT GCACAACCAC TACACGCAGA AGAGCCTCTC 12 51 CCTGTCTCCG GGTAAATGA (SEQ ID NO: 14) 50 hT^RII (G4S)2-hFc: Amino Acid Sequence 1   MDAMKRGLCC VLLLCGAVFV SPGATIPPHV QKSDVEMEAQ KDEIICPSCN 51   RTAHPLRHIN NDMIVTDNNG AVKFPQLCKF CDVRFSTCDN QKSCMSNCSI 101   TSICEKPQEV CVAVWRKNDE NITLETVCHD PKLPYHDFIL EDAASPKCIM 151   KEKKKPGETF FMCSCSSDEC NDNIIFSEEY NTSNPDTGGG GSGGGGSTHT 201   CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCWVD VSHEDPEVKF 2024205045   24 Jul 2024 10 15 20 25 35 40 45 50 251   NWYVDGVEVH NAKTKPREEQ YNSTYRWSV LTVLHQDWLN GKEYKCKVSN 301   KALPAPIEKT ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS 351   DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC 401   SVMHEALHNH YTQKSLSLSP GK (SEQ ID NO: 15) hTfiRII extended hmge-hFc: Nucleic Acid Sequence 1   ATGGATGCAA TGAAGAGAGG GCTCTGCTGT GTGCTGCTGC TGTGTGGAGC 51   AGTCTTCGTT TCGCCCGGCG CCACGATCCC ACCGCACGTT CAGAAGTCGG 101   ATGTGGAAAT GGAGGCCCAG AAAGATGAAA TCATCTGCCC CAGCTGTAAT 151   AGGACTGCCC ATCCACTGAG ACATATTAAT AACGACATGA TAGTCACTGA 201   CAACAACGGT GCAGTCAAGT TTCCACAACT GTGTAAATTT TGTGATGTGA 251   GATTTTCCAC CTGTGACAAC CAGAAATCCT GCATGAGCAA CTGCAGCATC 301   ACCTCCATCT GTGAGAAGCC ACAGGAAGTC TGTGTGGCTG TATGGAGAAA 351   GAATGACGAG AACATAACAC TAGAGACAGT TTGCCATGAC CCCAAGCTCC 401   CCTACCATGA CTTTATTCTG GAAGATGCTG CTTCTCCAAA GTGCATTATG 451   AAGGAAAAAA AAAAGCCTGG TGAGACTTTC TTCATGTGTT CCTGTAGCTC 501   TGATGAGTGC AATGACAACA TCATCTTCTC AGAAGAATAT AACACCAGCA 551   ATCCTGACAC CGGTGGTGGA CCCAAATCTT GTGACAAAAC TCACACATGC 601   CCACCGTGCC CAGCACCTGA ACTCCTGGGG GGACCGTCAG TCTTCCTCTT 651   CCCCCCAAAA CCCAAGGACA CCCTCATGAT CTCCCGGACC CCTGAGGTCA 701   CATGCGTGGT GGTGGACGTG AGCCACGAAG ACCCTGAGGT CAAGTTC1AAC 751   TGGTACGTGG ACGGCGTGGA GGTGCATAAT GCCAAGACAA AGCCGCGGGA 801   GGAGCAGTAC AACAGCACGT ACCGTGTGGT CAGCGTCCTC ACCGTCCTGC 851   ACCAGGACTG GCTGAATGGC AAGGAGTACA AGTGCAAGGT CTCCAACAAA 901   GCCCTCCCAG CCCCCATCGA GAAAACCATC TCCAAAGCCA AAGGGCAGCC 951   CCGAGAACCA CAGGTGTACA CCCTGCCCCC ATCCCGGGAG GAGATGACCA 1001   AGAACCAGGT CAGCCTGACC TGCCTGGTCA AAGGCTTCTA TCCCAGCGAC 1051   ATCGCCGTGG AGTGGGAGAG CAATGGGCAG CCGGAGAACA ACTACAAGAC 1101   CllCGCCTCCC GTGCTGGACT CCGACGGCTC CTTCTTCCTC TATAGCllAGC 1151   TCACCGTGGA CAAGAGCAGG TGGCAGCAGG GGAACGTCTT CTCATGCTCC 1201   GTGATGCATG AGGCTCTGCA CAACCACTAC ACGCAGAAGA GCCTCTCCCT 1251 GTCCCCGGGT AAATGA (SEQ ID NO: 16) hTpRIIextendedhinge-hFc: Amino Acid Sequence 1   MDAMKRGLCC VLLLCGAVFV SPGATIPPHV 51   RTAHP LRHIN NDMIVT DNN G AVKFPQ LCKF 101   TSICEKPQEV CVAVWRKNDE NITLETVCHD 151   KEKKKPGETF FMCSCSSDEC NDNIIFSEEY 201   PPCPAPELLG GPSVFLFPPK PKDTLMISRT 2 51   WYVDGVEVHN AKTKPREEQY NSTYRWSVL 301   ALPAPIEKTI SKAKGQPREP QVYTLPPSRE 351   IAVEWESNGQ PENNYKTTPP VLDSDGSFFL 401   VMHEALHNHY TQKSLSLSPG K (SEQ ID hTBRIl (G4S)5-hFc: Amino Acid Sequence 1 MDAMKRGLCC VLLLCGAVFV 51   RTAH P LRHIN NDMIVT DNNG 101 151 201 251 301 351 4 01 TSICEKPQEV KEKKKPGETF CVVVDVSHED QDWLNGKEYK N QVSLT C L VK TVDKSRWQQG CVAVWRKNDE FMCSCSSDEC GSTHTCPPCP PEVKFNWYVD CKVSNKALPA GEY P SDIAVE NVFSCSVMHE SPGATIPPHV AVKFPQLCKF NITLETVCHD NDNIIFSEEY APELLGGPSV GVEVHNAKTK PIEKTISKAK WESNGQPENN ALHNHYTQKS QKSDVEMEAQ CDVRFSTCDN PKLPYHDFIL NTSNPDTGGG PEVTCWDV TVLHQDWLNG EMTKNQVSLT YSKLTVDKSR N 0 : 17 ) KDEIICPSCN QKSCMSNCSI EDAASPKCIM PKSCDKTHTC SHEDPEVKFN KEYKCKVSNK CLVKGFYPSD WQQGNVFSCS QKSDVEMEAQ CDVRFSTCDN PKLPYHDFIL NTSNPDTGGG FLFPPKPKDT PREEQYNSTY GQPREPQVYT YKTTPPVLDS LSLSPGK (S KDEIICPSCN QKSCMSNCSI E DAAS P K CIM GSGGGGSGGG LMISRTPEVT RVVSVLTVLH LPPSREEMTK DGSFFLYSKL EQ ID NO: 4' 2024205045   24 Jul 2024 10 hTpRII (G4S)6-hFc: Amino Acid Sequence 1  MDAMKRGLCC VLLLCGAVFV 51   RTAH P LRHIN NDMIVT DNNG 101   TSICEKPQEV CV7WWRKNDE 151   KEKKKPGETF FMCSCSSDEC 201   GSGGGGSGGG GSGGGGSTHT 251   TPEVTCVVVD VSHEDPEVKF 301   LTVLHQDWLN GKEYKCKVSN 351   EEMTKNQVSL TCLVKGFYPS 401   LYSKLTVDKS RWQQGNVFSC NO :  4 5) SPGATIPPHV AVKFPQLCKF NTTLETVCHD NDNIIFSEEY CPPCPAPELL NWYVDGVEVH KALPAPIEKT DIAVEWESNG SVMHEALHNH QKSDVEMEAQ C DVR F S T C D N GGPSVFLFPP NAKTKPREEQ ISKAKGQPRE QPENNYKTTP YTQKSLSLSP KDEIICPSCN QKSCMSNCSI EDAASPKCIM GSGGGGSGGG KPKDTLMISR YNSTYRWSV PQVYTLPPSR PVLDSDGSFF GK (SEQ ID hTfiRII (G4S)5-hFc: Nucleotide Sequence 15 1 ATGGATGCAA, TGAAGAGAGG 20 51   AGTCTTCGTT TCGCCCGGCG 101   ATGTGGAAAT GGAGGCCCAG 151   AGGACTGCCC ATCCACTGAG 201   CAACAACGGT GCAGTCAAGT 251   GATTTTCCAC CTGTGACAAC 25 301   ACCTCCATCT GTGAGAAGCC 351   GAATGACGAG AACATAACAC 401   CCTACCATGA CTTTATTCTG 4 51   AAxGGAAAAAA AAAAJGCCTGG 5 01   T GAT GAGT GC AAT GACAACA 30 551   ATCCTGACAC CGGTGGAGGA 601   GGAAGTGGTG GAGGTGGTTC 651   ACCGTGCCCA GCACCTGAAC 701   CCCCAAAACC CAAGGACACC 751   TGCGTGGTGG TGGACGTGAG 35 8 01   GTA-CGTGGAC GGCGTGGAGG 851   AGCAGTACAA CAGCACGTAC 901   CAGGAxCTGGC TGAATGGCAA 951   CCTCCCAGCC CCCATCGAGA 10 01   GAGAACCACLA GGTGTACACC 40 1051   AACCAGGTCA GCCTGACCTG 1101   CGCCGTGGAG TGGGAGAGCA 1151   CGCCTCCCGT GCTGGACTCC 1201   ACCGTGGACA AGAGCAGGTG 12 51   GAT GOATGAG GOTCT GCACA 1301 CTCCGGGTAA ATGA. (SEQ GCTCTGCTGT CCACGATCCC AAAGATGAAA ACATATTAAT TTCCACAACT CAGAAATCCT ACAGGAAGTC TAGAGACAGT GAAGATGCTG TGAGACTTTC TCATCTTCTC GGTTCTGGTG TGGAGGTGGT TCCTGGGGGG CTCATGATCT CCACGAAGAC TGCATAATGC CGTGTGGTCA GGAGTACAAG AAAC CAT C T C CTGCCCCCAT CCTGGTCAAA ATGGGCAGCC GACGGCTCCT GCAGCAGGGG AC T A... Ac ID NO: 46) GTGCTGCTGC ACCGCACGTT TCATCTGCCC AACGACATGA GTGTAAATTT GCATGAGCAA TGTGTGGCTG TTGCCATGAC CTTCTCCAAA TTCATGTGTT AGAAGAATAT GT G GAGGTT C GGAAGTACTC ACCGTCAGTC CCCGGACCCC CCTGAGGTCA CAAGACAAAG GCGTCCTCAC TGCAAGGTCT CAAAGCCAAA CCCGGGAGGA GGCTTCTATC GGAGAACAAC TCTTCCTCTA AACGTCTTCT GCAGAAGAGC TGTGTGGAGC CA.GAAGTCGG CAGCTGTAAT TAGTCACTGA TGTGATGTGA CTGCAGCATC TAT GGAGAAA CCCAAGCTCC GTGCORTTATG CCTGILAGCTC AACACcAuc / ^. TGGAGGTG GA AC AC-Al' G C C C TTCCTCTTCC TGAGGTCACA AGTTCAACTG CCGCGGGAGG CGTCCTGCAC CCAAxCAAAGC GGGCAGCCCC GATGACCAAG CCAGCGACAT TACAAGACCA TAGGAAGCTC CATGCTCCGT CTCTCCCTGT 45 50 55 hTBRII (G4S)6-hFc: Nucleotide Sequence ‘     1 AxTGGATGCAA TGAAGAGAGG 51   AGTCTTCGTT TCGCCCGGCG 101   ATGTGGAAAT GGAGGCCCAG 151   AGGACTGCCC ATCCACTGAG 2 01   CAACAACGGT GCAGTCAAGT 251   GATTTTCCAC CTGTGACAAC 301   ACCTCCATCT GTGAGAAGCC 351   GAAiTGACGAG AAJSATAA.CAC 4 01   CCTA-1.CCATGK CTTTATTCTG 451   AAGGAAAAAA AAAAGCCTGG 5 01   T GAT GAGT GC AATGACAACA 551 ATCCTGACAC CGGTGGAGGT G C T C T G C T G T cCACGA'i eCc AAAGATGAAA ACATATTAAT TTCCACAACT CAGAAATCCT ACAGGAAGTC TAGAGACAGT GAAGATGCTG TGAGACTTTC TCATCTTCTC GGAAGTGGTG GTGCTGCTGC ACCGCACGTT TCATCTGCCC AACGACATGA GTGTAAATTT GCATGAGCAA TGTGTGGCTG TTGCCATGAC C T T C T C CAAA TTCATGTGTT AGAAGAATAT GAGGAGGTTC TGTGTGGAGC CA.GAAGTCGG CAGCTGTAAT TAGTCACTGA T GT GAT GT GA CTGCAGCATC TA.TGGAGAAA CCCAAGCTCC GTGCATCATG CCTGTAGCTC AACACCAGCA TGGTGGTGGA 2024205045   24 Jul 2024 601 651 7 01 751 801 851 901 951 1001 1051 1101 1151 1201 12 51 1301 GGTTCTGGAG T AC T CACACA CAGTCTTCCT ACCCCTGAGG GGTCAAGTTC CAAAGCCGCG CTCACCGTCC GGTCTCCAAC CCAAAGGGCA GAGGAGATGA CTATCCCAGC «6.17^ 1'Ac AA CTCTATAGCA cttctcatgc AGAGCCTCTC GTGGAGGAAG TGCCCACCGT CTTCCCCCCA TCACATGCGT AACTGGTACG G GA. G GAG GAG T G CAC CAG GA AAAGCCCTCC GCCCCGAGAA C C AA GAAC GA GACATCGCCG GACCACGCCT AGCTCACCGT TCCGTGATGC CCTGTCTCCG TGGTGGAGGT GCCCAGCACC AAACCCAAGG GGTGGTGGAC TGGACGGCGT TACAACAGCA CTGGCTGAAT CAGCCCCCAT GGTCAGCCTG TGGAGTGGGA. CCCGTGCTGG GGACAAGAGC ATGAGGCTCT GGTAAATGA GGTTCTGGAG TGAACTCCTG ACACCCTCA.T GTGAGCCACG GGAGGTGCAT CGTACCGTGT GGCAAGGAGT CGAGAAAACC ACACCCTGCC ACCTGCCTGG GAGCAATGGG ACTCCGAxCGG AGGTGGCAGC G CACAAC CAO (SEQ ID NO GTGGTGGAAG GGGGGACCGT GATCTCCCGG AAGACCCTGA AATGCCAAGA GGTCAGCGTC ACAAGTGCAA ATCTCCAAAG CCCATCCCGG TCAAAGGCTT CAGCCGGAGA CTCCTTCTTC AGGGGAACGT TACACGCAGA 47) The various constructs were successfully expressed in CHO cells and were purified to a high degree of p urity as determined by analytical size-exclusion chromatography and 20 SDS-PAGE. The hTpRII (G4S)2-hFc, hTpRII (G4S)3-hFc, hTpRII (G4S)4-hFc, hTpRII (G4S)5-hFc and hTpRII (G4S)6-hFc proteins displayed similarly strong stability' as determined by SDS-PAGE analysis when maintained in PBS for 13 days at 37°C. The hTpRII (G4S)2~hFc, hTpRII (G4S)3-hFc, hTpRII (G4S)4-hFc proteins were also maintained in rat, mouse or human serum and displayed similarly strong stability. 25 TpRII ECD vanants In addition to the TpRII domains included in the fusion proteins described above (e.g.. SEQ ID NO: 18), the disclosure also contemplates fusion proteins comprising alternative TpRII domains. For example, the fusion protein may comprise the wild-type hTpRIIShort(23-30   159) sequence shown below (SEQ ID NO: 27) or any of the other TpRII polypeptides disclosed below: 1 TIPPHVQKSV NNDMIVTDNN GAVKFPQLCK FCDVRFSTCD NQKSCMSNCS 51 ITSICEKPQE VCVAVWRKND ENITLETVCH DPKLPYHDFI LEDAASPKCI 101 MKEKKKPGET FFMCSCSSDE CNDNIIFSEE YNTSNPD (SEQ ID NO: 35      27) (1) The hTpRnShort(23-159 / Dl I OK) amino acid sequence shown below' (SEQ ID NO: 36), in which the substituted residue is underlined. 1 TIPPHVQKSV NNDMIVTDNN GAVKFPQLCK FCDVRFSTCD NQKSCMSNCS 2024205045   24 Jul 2024 51 ITSICEKPQE VCVAVWRKND ENITLETVCH DPKLPYHKFI LEDAASPKCI 101 MKEKKKPGET FFMCSCSSDE CNDNIIFSEE YNTSNPD (SEQ ID NO: 36) (2) The N-terminally truncated hTpRIIshort(29-159) amino acid sequence shown below (SEQ 5 ID NO: 28). 1 QKSVNNDMIV TDNNGAVKFP QLCKFCDVRF STCDNQKSCM SNCSITSICE 51 KPQEVCVAVW RKNDENITLE TVCHDPKLPY HDFILEDAAS PKCIMKEKKK 101 PGETFFMCSC SSDECNDNII FSEEYNTSNP D (SEQ ID NO: 28) (3) The N-terminally truncated hTpRIIShort(35-159) amino acid sequence shown below (SEQ 10 ID NO: 29). 1 DMIVTDNNGA VKFPQLCKFC DVRFSTCDNQ KSCMSNCSIT SICEKPQEVC 51 VAVWRKNDEN ITLETVCHDP KLPYHDFILE DAASPKCIMK EKKKPGETFF 101 MCSCSSDECN DNIIFSEEYN TSNPD (SEQ ID NO: 29) (4) The C-terminally truncated hTpRHshort(23-153) amino acid sequence shown below (SEQ 15 ID NO: 30). 1 TIPPHVQKSV NNDMIVTDNN GAVKFPQLCK FCDVRFSTCD NQKSCMSNCS 51  ITSICEKPQE VCVAVWRKND ENITLETVCH DPKLPYHDFI LEDAASPKCI 101  MKEKKKPGET FFMCSCSSDE CNDNIIFSEE Y (SEQ ID NO: 30) (5) The C-terminally truncated hTpRIIshort(23-153 / N70D) amino acid sequence shown below 20 (SEQ ID NO: 38), in which the substituted residue is underlined . 1 TIPPHVQKSV NNDMIVTDNN GAVKFPQLCK FCDVRFSTCD NQKSCMSDCS 51 ITSICEKPQE VCVAVWRKND ENITLETVCH DPKLPYHDFI LEDAASPKCI 101 MKEKKKPGET FFMCSCSSDE CNDNIIFSEE Y ID NO: 38) Applicants also envision five corresponding variants (SEQ ID NOs: 37, 33, 34, 39) 25 based on the wild-type hTpRniong(23-184) sequence shown above and below (SEQ ID NO: 49), in which the 25 amino-acid insertion is underlined. Note that splicing results in a conservative amino acid substitution (Vai—>Ile) at the flanking position C-terminal to the insertion. 1 TIPPHVQKSD VEMEAQKDEI ICPSCNRTAH PLRHINNDMI VTDNNGAVKF 2024205045   24 Jul 2024 51 PQLCKFCDVR FSTCDNQKSC MSNCSITSIC EKPQEVCVAV WRKNDENITL 101 ETVCHDPKLP YHDFILEDAA SPKCIMKEKK KPGETFFMCS CSSDECNDNI 151 IFSEEYNTSN PD (SEQ ID NO: 49) (1) The hTpRIIiong(23-184 / D135K) amino acid sequence shown below (SEQ ID NO: 37), in which the substituted residue is double underlined. 1 TIPPHVQKSD VEMEAQKDEI ICPSCNRTAH PLRHINNDMI VTDNNGAVKF 51 PQLCKFCDVR FSTCDNQKSC MSNCSITSIC EKPQEVCVAV WRKNDENITL 101 ETVCHDPKLP YHKFILEDAA SPKCIMKEKK KPGETFFMCS CSSDECNDNI 151 IFSEEYNTSN PD (SEQ ID NO: 37) (2) The N“terminally truncated hTpRIIiong(29-184) ammo acid sequence shown below (SEQ ID NO: 33). 1 QKSDVEMEAQ KDEIICPSCN RTAHPLRHIN NDMIVTDNNG AVKFPQLCKF 51 CDVRFSTCDN QKSCMSNCSI TSICEKPQEV CVAVWRKNDE NITLETVCHD 101 PKLPYHDFIL EDAASPKCIM KEKKKPGETF FMCSCSSDEC NDNIIFSEEY 151 NTSNPD (SEQ ID NO: 33) (3) The N-terminaHy truncated hTpRIIiong(60-184) amino acid sequence shown below (same as SEQ ID NO: 29). 1 DMIVTDNNGA VKFPQLCKFC DVRFSTCDNQ KSCMSNCSIT SICEKPQEVC 51 VAVWRKNDEN ITLETVCHDP KLPYHDFILE DAASPKCIMK EKKKPGETFF MCSCSSDECN DNIIFSEEYN TSNPD (same as SEQ ID NO: 29) (4) The C-terminally truncated hTpRIIiong(23-178) amino acid sequence shown below (SEQ ID NO: 34). 1  TIPPHVQKSD VEMEAQKDEI ICPSCNRTAH PLRHINNDMI VTDNNGAVKF 51  PQLCKFCDVR FSTCDNQKSC MSNCSITSIC EKPQEVCVAV WRKNDENITL 101  ETVCHDPKLP YHDFILEDAA SPKCIMKEKK KPGETFFMCS CSSDECNDNI 151 1FSEEY (SEQ ID NO: 34) (5) The C-terminally truncated hTpRIIiong(23- 178 / N95D) amino acid sequence shown below (SEQ ID NO: 39), in which the substituted residue is double underlined. 1 TIPPHVQKSD VEMEAQKDEI ICPSCNRTAH PLRHINNDMI VTDNNGAVKF 2024205045   24 Jul 2024 51 PQLCKFCDVR FSTCDNQKSC MSDCSITSIC EKPQEVCVAV WRKNDENITL 101 ETVCHDPKLP YHDFILEDAA SPKCIMKEKK KPGETFFMCS CSSDECNDNI 151 IFSEEY (SEQ ID NO: 39) Additional TpRII ECD variants include: 5   (A) The N- and C-terminally truncated hTpRIIShort(35-153) or hTpRlTiOng(60-178) amino acid sequence shown below (SEQ ID NO: 32). 1 DMIVTDNNGA VKFPQLCKFC DVRFSTCDNQ KSCMSNCSIT SICEKPQEVC 51 VAVWRKNDEN ITLETVCHDP KLPYHDFILE DAASPKCIMK EKKKPGETFF 101 MCSCSSDECN DNIIFSEEY (SEQ ID NO: 32) 10 (B) The N- and C-terminally truncated hTpRIIShort(29-153) amino acid sequence shown below (SEQ ID NO: 31). 1   QKSVNNDMIV TDNNGAVKFP QLCKFCDVRF STCDNQKSCM SNCSITSICE 51   KPQEVCVAVW RKNDENITLE TVCHDPKLPY HDFILEDAAS PKCIMKEKKK 15    101 PGETFFMCSC SSDECNDNII FSEEY (SEQ ID NO: 31) (C) The N- and C-terminally truncated hTpRIIiong(29-178) amino acid sequence shown below (SEQ ID NO: 35). 1 QKSDVEMEAQ KDEIICPSCN RTAHPLRHIN NDMIVTDNNG AVKFPQLCKF 20     51 CDVRFSTCDN QKSCMSNCSI TSICEKPQEV CVAVWRKNDE NITLETVCHD 101 PKLPYHDFIL EDAASPKCIM KEKKKPGETF FMCSCSSDEC NDNIIFSEEY (SEQ ID NO: 35) Any of the above variants (SEQ ID NO: 36, 28, 29, 30, 38, 37, 33, 34, 39, 32, 31, and 35) could incorporate an insertion of 36 amino acids (SEQ ID NO: 41) between the pair of 25 glutamate residues (positions 151 and 152 of SEQ ID NO: 1, or positions 176 and 177 of SEQ ID NO: 2) located near the C-terminus of the hTpRII ECD, as occurs naturally in tire hTpRII isoform C (Konrad et al., BMC Genomics 8:318, 2007). GRCKIRHIGS NNRLQRSTCQ NTGWESAHVM KTPGFR (SEQ ID NO: 41) As an example, the paired glutamate residues flanking the optional insertion site are 30 denoted below (underlined) for the hTpRIIsiwn(29-159) variant (SEQ ID NO: 28). 2024205045   24 Jul 2024 QK SVNNDMIV T DNNGAVKF P QLCKFCDVRF 51 KPQEVCVAVW RKNDENITLE TVCHDPKLPY STCDNQKSCM SNCSITSICE HDFILEDAAS PKCIMKEKKK '101 PGETFFMCSC SSDECNDNII FSEEYNTSNP D (SEQ ID NO: 28) Fc domain variants 5          While the constructs described above were generated with an Fc domain having the amino acid sequence of SEQ ID NO: 20, the disclosure contemplates hTpRII-hFc fusion proteins comprising alternative Fc domains, including a human TgG2 Fc domain (SEQ ID NO: 42, below) or full-length human IgGl Fc (hGlFc) (SEQ ID NO: 43, below). Optionally, a polypeptide unrelated to an Fc domain could be attached in place of the Fc domain. 10 r NW YVDGV lV NKGLPAPIEK SDIAVEWESN VAGPSVFLFP HNAKTKPREE TISKTKGQPR GQPENNYKTT PKPKDTLMIS QFNSTFRVVS EPQVYTLPPS PPMLDSDGSF RTPEVTCVVV V LTWHQDWL REEMTKNQVS FLYSKLTVDK DVSHEDPEVQ NGKEYKCKVS LTCLVKGFYP SRWQQGNVFS 201 CSVMHEALHN HYTQKSLSLS PGK (SEQ ID NO: 42) 1 51 101 151 20       2 01 GGPKSCDKTH DVSHEDPEVK NGKEYKCKVS LTCLVKGFYP S R WQQGNV F S TCPPCPAPEL FNWYVDGVEV NKALPAPIEK SDIAVEWESN CSVMHEALHN LGGPSVFLFP HNAKTKPREE TISKAKGQPR GQPENNYKTT HYTQKSLSLS PKPKDTLMIS QYNSTYRVVS EPQVYTLPPS PPVLDSDGSF PGK (SEQ RTPEVTCVVV VLTVLHQDWL REEMTKNQVS FLYSKLTVDK ID NO: 43) Leader sequence variants While the generated constructs described above included the TP A leader sequence. alternative leader sequences may be used, such as the native leader sequence (SEQ ID NO: 25   22- below) or the honey bee melittin (SEQ ID NO: 24- below) leader sequences. Native: MGRGLLRGLWPLHIVLWTR1AS (SEQ ID NO: 22) Honey bee melittin (HBML): MKFLVNVALVFMVVYISYIYA (SEQ ID NO: 24) Example 2. Differential ligand inhibition by receptor fusion protein variants in cell-30 based assay Affinities of TGFpi, TGFP2 and TGFP3 for hTpRII (G4S)2-hFc; hTpRII (G4S)3-hFc; hTpRII (G4S)4-hFc; hTpRII-hFc; and hTpRII extended hinge-hFc proteins were evaluated in vitro with a Biacore™ instrument, and the results are summarized in Figures 4A 2024205045   24 Jul 2024 and 4B. Each of the fusion proteins was capable of binding TGFpi and TGFP3 w'ith high affinity, but the constructs having linker lengths longer than or equal to (G4S)4 were surprisingly capable of binding to both TGFpi and TGFp3 with higher affinity than constructs having linker lengths shorter than (G4S)4. Binding between TGFP2 and any of the constructs was low' or transient. Deglycosylation of the constructs did not change binding. A reporter gene assay in A549 cells was used to determine the ability of hTpRII-hFc variants to inhibit activity of TGFpi, TGFP2 and TGFP3. This assay is based on a human lung carcinoma cell line transfected with a pGL3(CAGA)l 2 reporter plasmid (Dennler et al, 1998, EMBO 17: 3091-3100) as well as a Renilla reporter plasmid (pRLCMV)to control for transfection efficiency. The CAGA motif is present in the promoters of TGFp-responsive genes (for example, PAT-1), so this vector is of general use for factors signaling through SMAD2 and SMAD3. On the first day of the assay, A549 cells (ATCC®: CCL-185™) were distributed in 48-well plates. On the second day, a solution containing pGL3(CAGA)12, pRLCMV, X-tremeGENE 9 (Roche Applied Science), and OptiMEM (Invitrogen) was preincubated, then added to Eagle’s minimum essential medium (EMEM, ATCC®) supplemented with 0.1% BSA, which was applied to the plated cells for incubation overnight at37°C , 5% CO2. On the third day, medium was removed, and cells were incubated overnight at 37°C, 5% CO2 with a mixture of ligands and inhibitors prepared as described below'. Serial dilutions of test articles were made in a 48-well plate in assay buffer (EMEM t-0.1 % BSA). An equal volume of assay buffer containing the test ligand was added to obtain a final ligand concentration equal to the EC50 determined previously. Human TGFpi, human TGFP2, and human TGFP3 w'ere obtained from PeproTech. Test solutions were incubated at 37°C for 30 minutes, then a portion of tire mixture was added to all wells. After incubation with test solutions overnight, cells w'ere rinsed with phosphate-buffered saline, then lysed with passive lysis buffer (Promega E1941) and stored overnight at -70°C. On the fourth and final day, plates were warmed to room temperature with gentle shaking. Ceil lysates were transferred in duplicate to a chemiluminescence plate (96-well) and analyzed in a luminometer with reagents from a Dual-Luciferase Reporter Assay system (Promega E1980) to determine normalized luciferase activity. As illustrated m Figures 5A-5F, the hTpRII (G4S)2-hFc; hTpRII (G4S)3-hFc; hTpRII (G4S)4-hFc; hTpRII (G4S)5-hFc; hTpRII (G4S)6-hFc; hTpRII-hFc; and hTpRII extended hinge-hFc proteins all were capable of inhibiting both TGFpi and TGFP3. Interestingly, while there was a correlation between improved TGFpi and TGFp3 inhibition and linker -79- 2024205045   24 Jul 2024 length for the the hTpRII (G4S)2-hFc; hTpRII (G4S)3-hFc and hTpRII (G4S)4-hFc constructs (Figure 5E), this improvement trend appeared to have plateaued for hTpRII (G4S)5-hFc and hTpRII (G4S)6-hFc constructs (Figure 5F). INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or paten t was specifically and individually-indicated to be incorporated by reference. 10          While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. A Transforming Growth Factor-p Receptor II (TpRII) fusion polypeptide comprising:a) an extracellular domain of a TpRII portion;5          b) a heterologous portion, andc) a linker portion; wherein the linker is at least 10 amino acids in length; and wherein the TpRII extracellular domain portion comprises an amino acid sequence at least 80% identical to:i) a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and10          ending at any of positions 153 to 159 of SEQ ID NO: 1 orii) a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.

2. The polypeptide of claim 1, wherein the TBRli extracellular domain portion 15 comprises an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.

3. The polypeptide of claim 1, wherein the TpRII extracellular domain portion 20 comprises an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.

4. The polypeptide of claim 1, wherein the TpRII extracellular domain portion 25 comprises an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.

5. Tire polypeptide of claim 1, wherein the TpRII extracellular domain portion 30 comprises an amino acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.2024205045   24 Jul 20246. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portion comprises an amino acid sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.5           7. The polypeptide of claim 1, wherein the TpRII extracellular domain portioncomprises an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.10           8. The polypeptide of claim 1, wherein the TpRII extracellular domain portioncomprises an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.15           9. Tire polypeptide of claim 1, wherein the TpRII extracellular domain portioncomprises an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.20           10. The polypeptide of claim 1, wherein the TpRII extracellular domain portioncomprises an amino acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.25           11. The polypeptide of claim 1, wherein the TpRII extracellular domain portioncomprises an amino acid sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.

12. Tire polypeptide of claim 1, wherein the TpRII extracellular domain portion 30 comprises an amino acid sequence at least 80% identical to SEQ ID NO: 18.

13. The polypeptide of claim 1, wherein the TpRII extracellular domain portion comprises an amino acid sequence at least 90% identical to SEQ ID NO: 18.2024205045   24 Jul 202414. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portion comprises an amino acid sequence at least 95% identical to SEQ ID NO: 18.

15. The polypeptide of claim 1, wherein the TpRII extracellular domain portion 5 comprises an amino acid sequence at least 97% identical to SEQ ID NO: 18.

16. The polypeptide of claim 1, wherein the TpRII extracellular domain portion comprises the amino acid sequence of SEQ ID NO: 18.10           17. The polypeptide of claim. 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.15           18. Tire polypeptide of claim 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.20           19. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.25           20. The polypeptide of claim 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.30          21. The polypeptide of claim 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence beginning at any of positions 23 to 35 of SEQ ID NO: 1 and ending at any of positions 153 to 159 of SEQ ID NO: 1.2024205045   24 Jul 202422. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 80% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.

523. The polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 90% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.1024. The polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 95% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.1525. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 97% identical to a sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.2026. The polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence beginning at any of positions 23 to 60 of SEQ ID NO: 2 and ending at any of positions 178 to 184 of SEQ ID NO: 2.25           27. The polypeptide of claim 1, wherein the TpRII extracellular domain portionconsists of an amino acid sequence at least 80% identical to SEQ ID NO: 18.

28. The polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 90% identical to SEQ ID NO: 18.3029. The polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 95% identical to SEQ ID NO: 18.2024205045   24 Jul 202430. Hie polypeptide of claim 1, wherein the TpRII extracellular domain portion consists of an amino acid sequence at least 97% identical to SEQ ID NO: 18.

31. The polypeptide of claim 1, wherein the TpRII extracellular domain portion5 consists of the amino acid sequence of SEQ ID NO: 18.

32. The polypeptide of any one of claims 1-31, wherein the polypeptide comprises an N-terminal leader sequence.10          33. The polypeptide of claim 32, wherein the N-terminal leader sequencecomprises the amino acid sequence of any one of SEQ ID NOs: 22-24.

34. "lire polypeptide of claim 32 or 33, wherein tlie N-terminal leader sequence comprises the amino acid sequence of SEQ ID NO: 23.1535. Hie polypeptide of any one of claims 1 to 34, wherein the heterologous portion is an immunoglobulin Fc domain.

36. The polypeptide of claim 35, wherein the immunoglobulin Fc domain is a20 human immunoglobulin Fc domain.

37. Hie polypeptide of claim 35, wherein the heterologous portion comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 20.25          38. The polypeptide of claim 35, wherein the heterologous portion comprises anamino acid sequence that is at least 90% identical to SEQ ID NO: 20.

39. The polypeptide of claim 35, wherein the heterologous portion comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 20.3040. The polypeptide of claim 35, wherein the heterologous portion comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 20.2024205045   24 Jul 202441. Hie polypeptide of claim 35, wherein the heterologous portion comprises the amino acid sequence of SEQ ID NO: 20.

42. The polypeptide of any one of claims 1-41, wherein the linker is less than 25 5 amino acids in length.

43. The polypeptide of any one of claims 1-41, wherein the linker is between 10 and 25 amino acids in length.10          44. The polypeptide of any one of claims 1-41, wherein the linker is between 15and 25 amino acids in length.

45. The polypeptide of any one of claims 1-41, wherein the linker is between 17 and 22 amino acids in length.1546. The polypeptide of any one of claims 1-41, wherein the linker is 21 amino acids in length.

47. The polypeptide of any one of claims 1-41, wherein the linker comprises20 (GGGGS)n, wherein n == > 2.

48. Tire polypeptide of any one of claims 1-41, wherein the linker comprises (GGGGS)n, wherein n := > 3.25          49. The polypeptide of any one of claims 1-41, wherein the linker comprises(GGGGS)n, wherein n = > 4.

50. The polypeptide of any one of claims 1-44, wherein the linker comprises (GGGGS)n, wherein n^ > 5.3051. The polypeptide of any one of claims 1-50, wherein the linker comprises the amino acid sequence of SEQ ID NO: 21.2024205045   24 Jul 202452. Hie polypeptide of any one of claims 1-45, wherein the linker comprises the amino acid sequence of any one of SEQ ID NOs: 4-7.

53. The polypeptide of any one of claims 1-52, wherein the linker comprises the5 amino acid sequence of SEQ ID NO: 6.

54. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 11.1055. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11.15           56. Tire polypeptide of any one of claims 1-53, wherein the polypeptide comprisesan amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11.

57. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises 20 the amino acid sequence of SEQ ID NO: 11.

58. Tire polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 13, 53 or 56.2559. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 13, 53 or 56.30          60. Hie polypeptide of any one of claims 1-53, wherein the polypeptide comprisesan amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 13, 53 or 56.2024205045   24 Jul 202461. Hie polypeptide of any one of claims 1-53, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 13, 53 or 56.

62. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises 5 an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 15.

63. Ilie polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID 10 NO: 15.

64. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 15.1565. The polypeptide of any one of claims 1-53, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 15.

66. The polypeptide of any one of claims 1-65, wherein the TpRII polypeptide20 does not include amino acids 185-592 of SEQ ID NO: 2.

67. Ilie polypeptide of any one of claims 1-66, wherein the TpRII polypeptide does not include amino acids 1-22 of SEQ ID NO: 2.25           68. The polypeptide of any one of claims 1-67, wherein the polypeptide consistsof or consists essentially of:a) a TpRII polypeptide portion comprising an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids;30          b) a linker portion comprising an amino acid sequence that is at least 85%, 90%, 95%,97%, or 99% identical to the amino acid sequence of SEQ ID NO: 6 and no more than 5,4, 3, 2 or 1 additional amino acids;2024205045   24 Jul 2024c) a heterologous portion comprising an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids; andd) optionally a leader sequence (e.g., SEQ ID NO: 23).

569. "Ilie polypeptide of any one of claims 1-67, wherein tire polypeptide consists of or consists essentially of:a) a TpRII polypeptide portion comprising the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional ammo acids;10         b) a linker portion comprising the amino acid sequence of SEQ ID NO: 6 and no morethan 5, 4, 3, 2 or 1 additional amino acids;c) a heterologous portion comprising tire amino acid sequence of SEQ ID NO: 20 and no more than 25, 20, 15, 10, 5, 4, 3, 2, or 1 additional amino acids; andd) optionally a leader sequence (e.g., SEQ ID NO: 23).1570. Hie polypeptide of any one of claims 1-69, wherein the polypeptide comprises:a) an extracellular domain of a TpRII portion; wherein the extracellular domain comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to 20 the sequence of SEQ ID NO: 18;b) a heterologous portion, wherein the heterologous portion comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the sequence of SEQ ID NO: 20; andc) a linker portion connecting the extracellular domain and the heterologous portion;25 wherein the linker comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 6.

71. The polypeptide of any one of claims 1-70, wherein the polypeptide comprises:30          a) an extracellular domain of a TpRII portion; wherein the extracellular domaincomprises the amino acid sequence of SEQ ID NO: 18;b) a heterologous portion, wherein the heterologous portion comprises the amino acid sequence of SEQ ID NO: 20; and2024205045   24 Jul 2024c) a linker portion connecting the extracellular domain and the heterologous portion: wherein the linker comprises the amino acid sequence of SEQ ID NO: 6.

72. The polypeptide of any one of claims 1-71, wherein the polypeptide comprises 5 an amino acid sequence that is at least 85%, 90%, 95%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO: 48.

73. Tire polypeptide of any one of claims 1-72, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 48.1074. The polypeptide of claim 73, wherein the polypeptide does not include a leader sequence, or wherein the leader sequence has been removed.

75. The polypeptide of any one of claims 1-74, wherein the polypeptide includes 15 one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a famesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety’, and an amino acid conjugated to an organic derivatizing agent.20          76. The polypeptide of claim 75, wherein the polypeptide is glycosylated.

77. Tire polypeptide of any one of claims 1-75, wherein the polypeptide has a glycosylation pattern characteristic of expression of the polypeptide in CHO cells.25          78. The polypeptide of any one of claims 1-77, wherein the polypeptide bindshuman TGFpl with an equilibrium dissociation constant (Kd) less than 100 pM.

79. The polypeptide of any one of claims 1-78, wherein the polypeptide binds human TGFpi with an equilibrium dissociation constant (Kd) less than 75 pM.3080. The polypeptide of any one of claims 1-79, wherein the polypeptide binds human TGFp3 with an equilibrium dissociation constant (Kd) less than 60 pM.2024205045   24 Jul 202481. Hie polypeptide of any one of claims 1-80, wherein the polypeptide binds human TGFp3 with an equilibrium dissociation constant (Kd) less than 50 pM.

82. The polypeptide of any one of claims 1-81, wherein the polypeptide inhibits TGFpl with an ICso of less than 1.0 nM, as determined using a reporter gene assay.

83. The polypeptide of any one of claim s 1-81, wherein the polypeptide inhibits TGFpi with an ICso of less than 0.25 nM, as determined using a reporter gene assay.

84. The polypeptide of any one of cl aims 1-81, wherein the polypeptide inhibits TGFp l with an ICso of less than 0.1 nM, as determined using a reporter gene assay.

85. The polypeptide of any one of claims 1-81, wherein tire polypeptide inhibits TGFpi with an IC50 of less than 0.05 nM, as determined using a reporter gene assay.

86. Hie polypeptide of any one of claims 1-81, wherein the polypeptide inhibits TGFp3 with an ICso of less than 0.3 nM, as determined using a reporter gene assay.

87. The polypeptide of any one of claims 1-81, wherein the polypeptide inhibits TGFP3 with an ICso of less than 0.1 nM, as determined using a reporter gene assay.

88. Hie polypeptide of any one of claims 1-81, wherein the polypeptide inhibits TGFP3 with an ICso of less than 0.05 nM, as determined using a reporter gene assay.

89. The polypeptide of any one of claims 1-81, wherein the polypeptide inhibits TGFp3 with an IC50 of less than 0.04 nM, as determined using a reporter gene assay.

90. The polypeptide of any one of claims 82-88, wherein the reporter gene assay is a CAGA reporter assay.

91. A homodimer comprising two polypeptides as defined m any of claims 1-90.

92. An isolated polynucleotide comprising a coding sequence for the polypeptide of any one of claims 1-90.2024205045   24 Jul 202493. A recombinant polynucleotide comprising a promoter sequence operably linked to the polynucleotide of claim 92.

94. The polynucleotide of claim 92 or 93, wherein the polynucleotide comprises anucleotide sequence that is at least 80%, 85%, 90%, 95%, 97% or 100% identical to any one ofSEQ IDNOs: 10, 12 or 14.

95. A cell transformed with the polynucleotide of any one of claims 92-94.96.The cell of claim 95, wherein the cell is a mammalian cell.97."lire ceil of claim 95. wherein the cell is a CHO cell or a human cell.98.A pharmaceutical preparation comprising the polypeptide of any of claims 1 -90 or the homodimer of claim 91 and a pharmaceutically acceptable excipient.

99. A pharmaceutical preparation comprising the polypeptide of any one of claims 72-74 or a homodimer thereof, and a pharmaceutically acceptable excipient.

100. A method of modulating the response of a cell to a TGFp superfamily member, the method comprising exposing the cell to a polypeptide of any one of claims 1-90 or the homodimer of claim 91.

101. A method of treating a disease or condition associated with a TGFpsuperfamily member in a patient in need thereof, the method comprising administering to the patient an effective amount of a polypeptide of any of claims 1-90 or the homodimer of claim91.

102. The method of claim 101, wherein the TGFp superfamily member is TGFpi orTGFp3.

103. The method of claim 100 or 101, wherein the disease or condition is a cancer.2024205045   24 Jul 2024104. The method of claim 102, wherein the cancer is selected from stomach cancer, intestinal cancer, skin cancer, breast cancer, melanoma, bone cancer and thyroid cancer.

105. The method of claim 100 or 101, wherein the disease or condition is a fibrotic 5 or sclerotic disease or condition.

106. The method of claim 105, wherein the fibrotic or sclerotic disease or condition is selected from scleroderma, lupus erythematosis, pulmonary fibrosis, atherosclerosis, liver fibrosis, diffuse systemic sclerosis, glomerulonephritis, neural scarring, dermal scarring,10 radiation-induced fibrosis, hepatic fibrosis, idiopathic pulmonary’ fibrosis and myelofibrosis.

107. The method of claim 106, wherein the disease or condition is myelofibrosis.

108. The method of claim 107, wherein the disease or condition is selected from, the15   group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis.

109. The method of claim 107, wherein the disease or condition is selected from the group consisting of low risk, intermediate-1 risk, intermediate-2 risk, or high-risk20 myelofibrosis according to the International Prognostic Scoring System (1PSS) or to the to the dynamic IPSS (DIPSS).

110. The method of claim 106, wherein the disease or condition is idiopathic pulmonary fibrosis.25111. The method of claim 100 or 101, wherein the disease or condition is heart disease.

112. Tire method of claim 100 or 101, wherein the disease or condi tion is selected30 from hereditary hemorrhagic telangiectasia (HHT), Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, arterial tortuosity syndrome, preeclampsia, atherosclerosis, restenosis, and hypertrophic cardiomyopathy / congestive heart failure.2024205045   24 Jul 2024113. Hie method of claim 100 or 101, wherein the disease or condition is pulmonary hypertension.

114. The method of claim 113, wherein the pulmonary hypertension is Class I, Class II, Class III, or Class IV pulmonary hypertension as recognized by the World Health Organization.

115. Ilie method of claim 100 or 101, wherein the disease or condition is a kidney-associated disease or condition.

116. The method of claim 115, wherein the kidney-associated disease or condition is selected from the group consisting of: chronic kidney diseases (or failure), acute kidney diseases (or failure), primary kidney diseases, non-diabetic kidney diseases, glomerulonephritis, interstitial nephritis, diabetic kidney diseases, diabetic nephropathy, glomerulosclerosis, rapid progressive glomerulonephritis, renal fibrosis, Alport syndrome, IDDM nephritis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, renal interstitial fibrosis, focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, pauci-inimune rapid progressive glomerulonephritis, IgA nephropathy, polycystic kidney disease, Dent's disease, nephrocytinosis, Heymann nephritis, autosomal dominant (adult) polycystic kidney disease, autosomal recessive (childhood) polycystic kidney disease, acute kidney injury', nephrotic syndrome, renal ischemia, podocyte diseases or disorders, proteinuria, glomerular diseases, membranous glomerulonephritis, focal segmental glomerulonephritis, pre-eclampsia, eclampsia, kidney lesions, collagen vascular diseases, benign orthostatic (postural) proteinuria, IgM nephropathy, membranous nephropathy, sarcoidosis, diabetes mellitus, kidney damage due to drugs, Fabry's disease, aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, Sickle cell disease, hemoglobinuria, myoglobinuria, Wegener's Granulomatosis, Glycogen Storage Disease Type 1, chronic kidney disease, chronic renal failure, low' Glomerular Filtration Rate (GFR), nephroangiosclerosis, lupus nephritis, ANCA-positive pauci-immune crescentic glomerulonephritis, chronic allograft nephropathy, nephrotoxicity, renal toxicity', kidney necrosis, kidney damage, glomerular and tubular injury', kidney dysfunction, nephritic syndrome, acute renal failure, chronic renal failure, proximal tubal dysfunction, acute kidney transplant rejection, chronic kidneytransplant rejection, non-IgA mesangioproliferative glomerulonephritis, postinfectious2024205045   24 Jul 2024glomerulonephritis, vasculitides with renal involvement of any kind, any hereditary renal disease, any interstitial nephritis, renal transplant failure, kidney cancer, kidney disease associated with other conditions (e.g., hypertension, diabetes, and autoimmune disease), Dent's disease, nephrocytinosis, Heymann nephritis, a primary7 kidney disease, a collapsing glomerulopathy, a dense deposit disease, a cryoglobulinemia-associated glomerulonephritis, an Henoch-Schonlein disease, a postinfectious glomerulonephritis, a bacterial endocarditis, a microscopic polyangitis, a Churg-Strauss syndrome, an anti-GBM-antibody mediated glomerulonephritis, amyloidosis, a monoclonal immunoglobulin deposition disease, a fibrillary glomerulonephritis, an immunotactoid glomerulopathy, ischemic tubular injury, a medication-induced tubulo-interstitial nephritis, atoxic tubulo-interstitial nephritis, an infectious tubulo-interstitial nephritis, abacterial pyelonephritis, a viral infectious tubulointerstitial nephritis which results from a polyomavirus infection or an HIV infection, a metabolic-induced tubulo-interstitial disease, a mixed connective disease, a cast nephropathy, a crystal nephropathy which may results from urate or oxalate or drug-induced crystal deposition, an acute cellular tubulo-interstitial allograft rejection, a tumoral infiltrative disease which results from a lymphoma or a post-transplant lymphoproliferative disease, an obstructive disease of the kidney, vascular disease, a thrombotic microangiopathy, a nephroangiosclerosis, an atheroembolic disease, a mixed connective tissue disease, a polyarteritis nodosa, a calcineurin-inhibitor induced-vascular disease, an acute cellular vascular allograft rejection, an acute humoral allograft rejection, early renal function decline (ER_FD), end stage renal disease (ESRD), renal vein thrombosis, acute tubular necrosis, acute interstitial nephritis, established chronic kidney disease, renal artery7 stenosis, ischemic nephropathy, uremia, drug and toxin-induced chronic tubulointerstitial nephritis, reflux nephropathy, kidney stones, Goodpasture's syndrome, normocytic normochromic anemia, renal anemia, diabetic chronic kidney disease, IgG4-related disease, von Hippel-Lindau syndrome, tuberous sclerosis, nephronophthisis, medullary' cystic kidney disease, renal cell carcinoma, adenocarcinoma, nephroblastoma, lymphoma, leukemia, hyposialylation disorder, chronic cyclosporine nephropathy, renal reperfusion injury, renal dysplasia, azotemia, bilateral arterial occlusion, acute uric acid nephropathy, hypovolemia, acute bilateral obstructive uropathy, hypercalcemic nephropathy, hemolytic uremic syndrome, acute urinary retention, malignant nephrosclerosis, postpartum glomerulosclerosis, scleroderma, nonGoodpasture's anti-GBM disease, microscopic polyarteritis nodosa, allergic granulomatosis, acute radiation nephritis, post-streptococcal glomerulonephritis, Waldenstrom's macroglobulinemia, analgesic nephropathy, arteriovenous fistula, arteriovenous graft,2024205045   24 Jul 2024dialysis, ectopic kidney, medullary sponge kidney, renal osteodystrophy, solitary kidney, hydronephrosis, microalbuminuria, uremia, haematuria, hyperlipidemia, hypoalbummaemia, lipiduria, acidosis, hyperkalemia, and edema.5          117. The method of claim 115, wherein the kidney-associated disease or conditionis chronic kidney disease.

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