Chimeric TGFβ Receptor Fusion Proteins for IL-2 Signal Conversion
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Solution Overview
Problem
Existing adoptive cell therapies for cancer and other diseases, particularly in the context of solid tumors, require improved strategies to enhance cellular immunotherapy by converting the suppressive TGFβ signal into a beneficial IL-2 signal to promote T cell proliferation and effector function.
Innovation Solution
Development of chimeric fusion proteins comprising a TGFβ receptor extracellular domain, a transmembrane domain, and an IL-2 receptor intracellular signaling domain, which convert TGFβ input into an IL-2 signal in host cells, thereby promoting proliferation and effector function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional adoptive cell therapies are used, then T cell therapy is provided, but TGFβ suppressive signals inhibit T cell proliferation and effector function
Solution Approach 1:
The patent converts the harmful TGFβ suppressive signal into a beneficial IL-2 proliferative signal by engineering chimeric fusion proteins that function as TGFβ decoy receptors. These fusion proteins contain the extracellular ligand-binding domain of TGFβ receptors coupled to the intracellular signaling domain of IL-2 receptors, thereby transducing TGFβ binding events into IL-2 signaling that promotes T cell proliferation and effector function rather than suppression
Solution Approach 2:
The chimeric fusion proteins serve as intermediary molecules that intercept TGFβ signals and transform them into beneficial IL-2 signals. The fusion proteins mediate the conversion by combining TGFβ receptor extracellular domains (which bind TGFβ) with IL-2 receptor intracellular signaling domains (which transmit proliferative signals), effectively acting as a signal transduction bridge that converts harmful suppression into beneficial activation
2Productivity
If chimeric fusion proteins are engineered to convert TGFβ signal to IL-2 signal, then T cell proliferation is enhanced, but protein structure complexity increases
Solution Approach 1:
The patent merges two distinct receptor domains into a single chimeric fusion protein: the extracellular ligand-binding domain of TGFβ receptors (TGFβR1 or TGFβR2) is fused to the intracellular signaling domain of IL-2 receptors (IL-2Rβ or IL-2Rγ). This merging creates a unified protein structure that can both bind TGFβ and transmit IL-2 signaling, thereby enhancing T cell proliferation while maintaining a manageable single-protein format rather than requiring multiple separate components
Data Source
AI summary
The present disclosure provides fusion proteins with novel signaling properties. Disclosed embodiments include fusion proteins that comprise an extracellular component that is capable of binding to a TGFβ polypeptide, a transmembrane component, and an intracellular component comprising a cytoplasmic domain from an IL-2Rβ or IL-2Rγ protein. Certain embodiments include a TGFβR intracellular overhang or overhang sequence extending from a TGFβR transmembrane domain, N-terminal to the IL-2R cytoplasmic domain. In response to TGFβ, the fusion proteins can initiate an IL-2 signal in a host cell, promoting, for example, proliferation of the host cells. Recombinant host cells expressing the fusion proteins, and an optional antigen-binding protein such as a TCR or a CAR, are provided. Also provided are polynucleotides encoding the fusion proteins, and vectors that comprise the polynucleotides. Also provided are compositions and methods comprising the same.