Transforming growth factor-beta (TGF-beta) receptor type II fusion polypeptides
Inventors
Kumar, Ravindra • Sako, Dianne S.
Assignees
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Publication Number
US-12195519-B2
Publication Date
2025-01-14
Expiration Date
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.
Core Innovation
Transforming Growth Factor-b2 receptor II fusion polypeptides are provided as soluble forms comprising a Tb2RII extracellular domain portion and a heterologous portion. The Tb2RII extracellular domain portion comprises an amino acid sequence that is at least 85% identical to amino acids 23-184 of SEQ ID NO: 2, and the fusion further comprises a linker portion that comprises (GGGGS)n, wherein n34, to connect the extracellular domain portion to the heterologous portion.
The heterologous portion can include an immunoglobulin Fc domain, and a homodimer format is described, where each polypeptide comprises the Tb2RII extracellular domain portion, the heterologous portion, and the linker portion comprising (GGGGS)n with n34. The disclosure also describes preferred extracellular domain truncations and related identity thresholds, including identity levels raised to at least 90% and in further refinements to at least 97% or at least 95% for homodimer formats.
The document describes tuning of Fc domains to tune receptor binding and effector function, and it describes longer linkers improving binding to TGF-b21/TGF-b23, including potency and affinity metrics such as Kd and IC50. In particular, the polypeptides are described as inhibiting TGF-b21 and/or TGF-b23, including reporting inhibition potency thresholds using a CAGA reporter assay and related measures.
Claims Coverage
The partial claim set provided contains two independent claims. Each independent claim centers on a Tb2RII fusion polypeptide or homodimer architecture that combines a Tb2RII extracellular domain portion, a heterologous portion, and a (GGGGS)n linker with n34, with independent-level sequence identity constraints for the Tb2RII extracellular domain portion.
Tb2RII fusion polypeptide architecture with high-identity extracellular domain and (GGGGS)n linker
A Transforming Growth Factor-b2 Receptor II (Tb2RII) fusion polypeptide comprising a Tb2RII 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; a heterologous portion; and a linker portion comprising (GGGGS)n, wherein n34.
Tb2RII homodimer architecture with high-identity extracellular domain and (GGGGS)n linker
A homodimer comprising two polypeptides, each polypeptide comprising a Tb2RII extracellular domain portion comprising an amino acid sequence that is at least 90% identical to the amino acids 23-184 of SEQ ID NO: 2; a heterologous portion; and a linker portion comprising (GGGGS)n, wherein n34.
Across the two independent claims, the inventive coverage is directed to Tb2RII extracellular-domain-containing fusion polypeptides and homodimers that use a (GGGGS)n linker with n34 and include a heterologous portion, while enforcing minimum sequence identity constraints for the Tb2RII extracellular domain portion.
Stated Advantages
Longer linkers improve binding to TGF-b21/TGF-b23.
The polypeptides inhibit TGF-b21 and/or TGF-b23, with defined potency/affinity metrics (Kd and IC50 thresholds) described in the document.
Documented Applications
Therapeutic use in multiple fibrotic and inflammatory diseases, including chronic kidney disease (CKD) and CKD-MBD (chronic kidney disease mineral bone disorder), and myelofibrosis.
Broader therapeutic indications described as autoimmune, metabolic, infectious/transplant-related, COPD/idiopathic pulmonary fibrosis/asthma, and pulmonary hypertension.
Therapeutic use is described for TGFb superfamily associated disorders including cancer and fibrotic diseases (e.g., pulmonary fibrosis and myelofibrosis).
Therapeutic use is described for vascular/cardiac and kidney disorders.
Therapeutic use is described for pulmonary hypertension.
Use in pharmaceutical compositions with systemic or local administration and co-therapy options, including described delivery concepts such as parenteral carriers, implant/device delivery, targeted liposomes, and gene therapy approaches for in vivo production via targeted retroviral vectors or liposome-based delivery.
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