Granted Patent
B2
US 12,195,519 · App. 17/245,581 · Granted Jan 14, 2025
Transforming growth factor-beta (TGF-beta) receptor type II fusion polypeptides
Assignee:
Acceleron Pharma Inc.
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Abstract
In certain aspects, the present disclosure relates to TβRII fusion polypeptides comprising a heterologous portion and 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.
Claims (44)
1. A Transforming Growth Factor-β Receptor II (TβRII) fusion polypeptide comprising:
a) a TβRII extracellular domain portion comprising an amino acid sequence that is at least 85% identical to the amino acids 23-184 of SEQ ID NO: 2;
b) a heterologous portion, and
c) a linker portion that comprises (GGGGS)n, wherein n≥4.
2. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 90% identical to amino acids 23-184 of SEQ ID NO: 2.
3. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 95% identical to amino acids 23-184 of SEQ ID NO: 2.
4. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 97% identical to amino acids 23-184 of SEQ ID NO: 2.
5. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 96% identical to SEQ ID NO: 18.
6. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 98% identical to SEQ ID NO: 18.
7. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises an amino acid sequence at least 99% identical to SEQ ID NO: 18.
8. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion consists of SEQ ID NO: 18.
9. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion consists essentially of SEQ ID NO: 18.
10. The polypeptide of claim 1 , wherein the TβRII extracellular domain portion comprises the amino acid sequence of SEQ ID NO: 18.
11. The polypeptide of claim 1 , wherein the polypeptide comprises an N-terminal leader sequence.
12. The polypeptide of claim 11 , wherein the N-terminal leader sequence comprises the amino acid sequence of SEQ ID NO: 23.
13. The polypeptide of claim 1 , wherein the heterologous portion is an immunoglobulin Fc domain.
14. The polypeptide of claim 13 , wherein the immunoglobulin Fc domain is a human immunoglobulin Fc domain.
15. The polypeptide of claim 13 , wherein the heterologous portion comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 20.
16. The polypeptide of claim 13 , wherein the heterologous portion comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 20.
17. The polypeptide of claim 13 , wherein the heterologous portion comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 20.
18. The polypeptide of claim 13 , wherein the heterologous portion comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 20.
19. The polypeptide of claim 13 , wherein the heterologous portion comprises the amino acid sequence of SEQ ID NO: 20.
20. The polypeptide of claim 1 , wherein the linker comprises the amino acid sequence of SEQ ID NO: 6.
21. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 48.
22. The polypeptide of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 48.
23. The polypeptide of claim 1 , wherein the polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.
24. The polypeptide of claim 1 , wherein the polypeptide, when in dimer form, inhibits TGFβ1 with an IC 50 of between 0.02 nM and 1.0 nM, as determined using a reporter gene assay, or wherein the polypeptide inhibits TGFβ3 with an IC 50 of between 0.02 nM and 1.0 nM, as determined using a reporter gene assay.
25. The polypeptide of claim 24 , wherein the reporter gene assay is a CAGA reporter assay.
26. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 52.
27. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 53.
28. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 54.
29. The polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 55.
30. A pharmaceutical preparation comprising the polypeptide of claim 1 and a pharmaceutically acceptable excipient.
31. The pharmaceutical preparation of claim 30 , wherein the polypeptide is present in the preparation as a homodimer.
32. A homodimer comprising two polypeptides, wherein each polypeptide comprises the polypeptide of claim 22 .
33. A homodimer comprising two polypeptides, each polypeptide comprising
a) a TβRII extracellular domain portion comprising an amino acid sequence that is at least 90% identical to amino acids 23-184 of SEQ ID NO: 2;
b) a heterologous portion, and
c) a linker portion that comprises (GGGGS)n, wherein n≥4.
34. The homodimer of claim 33 , wherein the extracellular domain portion comprises an amino acid sequence that is at least 95% identical to amino acids 23-184 of SEQ ID NO: 2.
35. The homodimer of claim 33 , wherein
the extracellular domain portion comprises amino acids 23-184 of SEQ ID NO: 2;
the heterologous portion comprises an immunoglobulin Fc domain; and
the linker comprises SEQ ID NO: 59.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 3, 2021
From: KUMAR, RAVINDRA; SAKO, DIANNE S.
To: ACCELERON PHARMA INC.
Reel/Frame 058007/0198 →
Continuity (5)
Provisional Application
62578674
· Oct 30, 2017
Provisional Application
62510422
· May 24, 2017
Provisional Application
62501229
· May 4, 2017
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