Chimeric Tim4 Receptors with Costimulation Against T-Cell Exhaustion
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Solution Overview
Problem
Existing engineered T cells, such as those expressing chimeric antigen receptors (CARs), can develop exhaustion due to prolonged antigen exposure, leading to impaired effector function and persistence of tumor cells.
Innovation Solution
Development of chimeric T-cell immunoglobulin mucin protein 4 (Tim4) receptors that confer cytotoxic activity and costimulatory signals upon binding to phosphatidylserine, reducing T cell exhaustion and enhancing immune responses through multiple signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If engineered T cells express chimeric antigen receptors (CARs) to enhance tumor cell killing, then cytotoxic activity is improved, but T cell exhaustion develops leading to impaired effector function
Solution Approach 1:
The patent combines cytotoxic activity with costimulatory signaling in a single chimeric Tim4 receptor construct. The extracellular domain binds phosphatidylserine on tumor cells while the intracellular domain contains costimulatory signaling motifs that simultaneously provide tumor cell killing and prevent T cell exhaustion, merging two previously separate functions into one receptor
Solution Approach 2:
The chimeric Tim4 receptor serves multiple functions: it mediates cytotoxic activity against phosphatidylserine-expressing tumor cells, provides costimulatory signals to prevent exhaustion, and enhances T cell persistence. This multi-functional design allows a single receptor to address both the need for strong anti-tumor activity and the need for sustained effector function
2Productivity
If T cells are exposed to prolonged antigen stimulation to eliminate tumor cells, then tumor cell clearance is improved, but T cell exhaustion occurs resulting in poor proliferation and metabolic defects
Solution Approach 1:
The costimulatory signaling domain in the chimeric Tim4 receptor provides continuous beneficial signals during prolonged antigen exposure. This continuous costimulation maintains T cell metabolism, proliferation capacity, and effector function throughout the extended period needed for complete tumor cell clearance, preventing the development of exhaustion
Solution Approach 2:
The patent changes the signaling parameters of T cell activation by incorporating costimulatory motifs into the intracellular domain. This modification alters the signaling profile from单纯的 cytotoxic activation to a balanced activation-costimulation pattern that sustains T cell function over prolonged periods without inducing exhaustion
3Reliability
If chimeric Tim4 receptors provide costimulatory signals through multiple signaling pathways, then T cell exhaustion is reduced, but receptor structure complexity increases
Solution Approach 1:
Multiple costimulatory signaling pathways are merged into a single intracellular domain of the chimeric Tim4 receptor. This consolidation provides diverse costimulatory signals through one integrated structure rather than requiring multiple separate receptors or signaling complexes, thereby reducing overall system complexity while maintaining exhaustion resistance
Data Source
AI summary
The present disclosure relates to chimeric Tim4 receptors, host cells modified to include chimeric Tim4 receptor molecules, and methods of making and using such receptor molecules and modified cells.