TGF-beta receptors and methods of use
Inventors
Wyman, Sarah • Emtage, Peter • Romain, Gabrielle
Assignees
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Publication Number
US-12109235-B2
Publication Date
2024-10-08
Expiration Date
Abstract
Provided herein are engineered receptors involved in cytokine signaling. Also provided herein are engineered receptors for modulating TGF-β signaling, methods of modulating TGF-β signaling and treating cancer using chimeric antigen receptors.
Core Innovation
The invention relates to a recombinant polypeptide consisting of an extracellular domain (ECD) from a Transforming Growth Factor-beta (TGF-β) receptor, a transmembrane domain (TMD), and an intracellular domain (ICD) consisting of an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6. The recombinant polypeptide binds to TGF-β1 and functions as a dominant negative inhibitor of TGF-β receptor signaling. The receptor architecture is described in terms of ECD-TMD-ICD, including truncation after the transmembrane domain and modifications to remove signaling and phosphorylation-related residues.
The dominant-negative approach is described as modulating TGF-β/pSMAD immunosuppression in the tumor microenvironment. The document links dominant-negative suppression of TGF-β-driven pSMAD signaling to impaired immunosuppression, and it frames this as enabling engineered T-cell immunotherapies. The engineered receptors are also presented with sequence-identity-based options using multiple SEQ ID NOs for selecting components and defining variant degrees of sequence identity.
The invention further connects TGF-β-mediated T cell suppression to impaired CAR expansion and persistence, motivating combination use in engineered T-cell immunotherapies. It describes use within T-cell constructs including TCR or CAR, and it specifies that a CAR can be co-expressed together with the dominant-negative TGF-β receptor. Tumor antigen targeting examples are provided, including CAR binding to CD19, CD20, PSMA, GPC3, CLL-1, and additional tumor antigen targets referenced in the document.
Claims Coverage
The independent claim covers a recombinant dominant-negative TGF-β receptor polypeptide built from ECD-TMD-ICD, with TGF-β1 binding and dominant-negative inhibition. The dependent claims refine the independent claim by narrowing ECD selection, specifying sequence-identity thresholds for ECD and TMD relative to SEQ IDs, modifying the ICD to lack wild-type signaling/phosphorylation residues, and adding expression-vector and CAR features with defined tumor antigen binding targets.
Dominant-negative TGF-β receptor polypeptide with TGF-β1 binding
A recombinant polypeptide consisting of an extracellular domain (ECD) from a Transforming Growth Factor-beta (TGF-β) receptor, a transmembrane domain (TMD), and an intracellular domain (ICD) consisting of an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6, wherein the recombinant polypeptide binds to TGF-β1 and functions as a dominant negative inhibitor of TGF-β receptor.
Recombinant polypeptide with selected TGF-β receptor ECD
The recombinant polypeptide includes an ECD selected from TGF-βRI or TGF-βRII.
Sequence-identity constraints for ECD and TMD
The recombinant polypeptide is defined where the ECD has at least 75% sequence identity to SEQ ID NO: 15 and the TMD has at least 75% sequence identity to SEQ ID NO: 16.
ICD modification removing wild-type signaling/phosphorylation residues
The intracellular domain (ICD) is modified to lack amino acid residues that drive signaling and phosphorylation found in the wild-type TGF-β receptor.
Expression vector encoding a CAR
An expression vector further includes a nucleic acid sequence that encodes a chimeric antigen receptor (CAR).
CAR tumor-antigen binding target selection
The CAR binds to a tumor antigen selected from CD19, CD20, PSMA, PCMA, CLL-1, or GPC3.
Overall, the claim set centers on dominant-negative TGF-β receptor polypeptides that bind TGF-β1 via an ECD-TMD-ICD architecture, with ICD defined by sequence identity to SEQ ID NO: 6 and further dependent narrowing through ECD/TMD sequence-identity constraints and ICD residue removal. Additional dependents add expression-vector implementation and incorporation of a CAR that targets specified tumor antigens.
Stated Advantages
Dominant negative inhibition of TGF-β receptor signaling through binding to TGF-β1.
Reduces TGF-β1-induced suppressive pSMAD2/3 signaling.
Partially restores TGF-β1 signaling/function.
Preserves or boosts effector cytokine production, including IFN-γ.
Supports T cell expansion under repeated target stimulation.
Provides tumor control in xenograft models.
Improved CAR T-cell function in the presence of TGF-β mediated suppression.
Documented Applications
Use of CAR constructs combined with DN TGF-β receptor (CAR-DN TGF-β receptor constructs) to reduce suppressive TGF-β signaling and improve CAR T-cell function.
CAR/TCR-modified T cells expressing dominant-negative TGF-β receptors to counteract TGF-β1-induced suppressive signaling and maintain effector function and expansion during repeated target stimulation.
Modulating TGF-β/pSMAD immunosuppression in the tumor microenvironment.
Use in engineered T-cell immunotherapies including TCR or CAR, including co-expression of the dominant-negative TGF-β receptor with a CAR.
Tumor antigen targeting using CAR binding to CD19, CD20, PSMA, PCMA, CLL-1, or GPC3.
In vivo tumor control in xenograft models (including comparisons across different CAR targets and co-stimulatory domains).
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