Methods of treating a sclerotic disorder by administering a transforming growth factor beta receptor type II fusion polypeptide
In certain aspects, the present disclosure relates to polypeptides comprising a truncated, ligand-binding portion of the extracellular domain of TβRII polypeptide useful to selectively antagonize a TβRII ligand. The disclosure further provides compositions and methods for use in treating or preventing TGFβ associated disorders.
1. A method of treating a subject having a sclerotic disorder, comprising administering to the subject a Transforming Growth Factor β Receptor II (TβRII) fusion polypeptide consisting of:
a) a first amino acid sequence from the extracellular domain of TβRII, wherein the first amino acid sequence consists of an amino acid sequence at least 95% identical to SEQ ID NO: 13;
b) a heterologous portion; wherein the heterologous portion is an immunoglobulin Fc domain; and
c) a linker joining the first amino acid sequence to the immunoglobulin Fc domain; wherein the fusion polypeptide does not include a signal sequence and does not include
the amino acids corresponding to amino acids 185-592 of SEQ ID NO: 6;
wherein the sclerotic disorder is associated with dysregulated TGFβ1 or TGFβ3 signaling;
and wherein the fusion polypeptide binds Transforming Growth Factor β1 or Transforming Growth Factor β3.
2. The method of claim 1 , wherein the first amino acid sequence consists of the amino acid sequence of SEQ ID NO: 13.
3. The method of claim 1 , wherein the polypeptide is glycosylated.
4. The method of claim 1 , wherein the polypeptide has a glycosylation pattern characteristic of expression of the polypeptide in CHO cells.
5. The method of claim 1 , wherein the immunoglobulin Fc domain comprises the amino acid sequence of SEQ ID NO: 21.
6. The method of claim 1 , wherein the fusion polypeptide binds Transforming Growth Factor β1 and Transforming Growth Factor β3.
7. The method of claim 1 , wherein the sclerotic disorder is any one or more of scleroderma, atherosclerosis, progressive systemic sclerosis (PSS), or diffuse systemic sclerosis.
8. The method of claim 1 , wherein the sclerotic disorder is diffuse systemic sclerosis.
9. A method of treating a subject having a sclerotic disorder, comprising administering to the subject a Transforming Growth Factor β Receptor II (TβRII) fusion polypeptide comprising a first amino acid sequence from the extracellular domain of TβRII and a heterologous amino acid sequence, wherein the first amino acid sequence consists of an amino acid sequence at least 95% identical to SEQ ID NO: 13; wherein the heterologous amino acid sequence comprises the amino acid sequence of any one of SEQ ID NOs: 19, 20 or 21; wherein the sclerotic disorder is associated with dysregulated TGFβ1 or TGFβ3 signaling; and wherein the fusion polypeptide does not include a signal sequence and does not include the amino acids corresponding to amino acids 185-592 of SEQ ID NO: 6; and wherein the fusion polypeptide binds Transforming Growth Factor β1 or Transforming Growth Factor β3.
10. The method of claim 9 , wherein the heterologous amino acid sequence is joined to the TβRII polypeptide by a linker.
11. The method of claim 9 , wherein the first amino acid sequence consists of the amino acid sequence of SEQ ID NO: 13.
12. The method of claim 9 , wherein the polypeptide is glycosylated.
13. The method of claim 9 , wherein the polypeptide has a glycosylation pattern characteristic of expression of the polypeptide in CHO cells.
14. The method of claim 9 , wherein the immunoglobulin Fc domain comprises the amino acid sequence of SEQ ID NO: 21.
15. The method of claim 9 , wherein the fusion polypeptide binds Transforming Growth Factor β1 and Transforming Growth Factor β3.
16. The method of claim 9 , wherein the sclerotic disorder is any one of scleroderma, atherosclerosis, progressive systemic sclerosis (PSS), or diffuse systemic sclerosis.
17. The method of claim 9 , wherein the sclerotic disorder is diffuse systemic sclerosis.