Mesothelin-Specific TCRs for Intermediate Affinity Cancer Therapy
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Solution Overview
Problem
Current adoptive cell therapies targeting cancer with high-affinity T cell receptors (TCRs) face challenges of lethal toxicity due to off-tumor recognition and T cell exhaustion, highlighting the need for TCRs with intermediate affinity that can effectively target mesothelin-expressing tumors without excessive toxicity.
Innovation Solution
Development of mesothelin-specific binding proteins, including T cell receptors (TCRs), that bind mesothelin with intermediate affinity, allowing for antigen-specific tumor lysis without high off-tumor toxicity, and methods for delivering these proteins to target cells to enhance immune response, including co-expression of molecules that improve immune function and reduce suppressive signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high-affinity TCRs are used to target cancer, then anti-tumor activity is improved, but off-tumor toxicity increases
Solution Approach 1:
The patent applies parameter changes by optimizing TCR affinity to fall within an intermediate range rather than maximizing it. Specifically, the TCRs are designed to bind mesothelin with sufficient affinity to recognize tumor cells but not so high as to cause off-tumor toxicity. This involves adjusting binding kinetics parameters (KD, kon, koff) to achieve the optimal balance between efficacy and safety.
Solution Approach 2:
The patent applies partial action by using TCRs with intermediate rather than maximum affinity. The TCRs are designed to provide sufficient tumor recognition and lysis without the excessive binding strength that would lead to off-tumor effects. This partial optimization of affinity resolves the contradiction between anti-tumor activity and toxicity.
2Reliability
If high-affinity TCRs are used to increase T cell recognition, then tumor lysis is improved, but T cell exhaustion increases
Solution Approach 1:
The patent applies parameter changes by adjusting TCR affinity parameters to an intermediate range that prevents excessive T cell activation. High-affinity TCRs cause continuous strong signaling that leads to exhaustion, while intermediate-affinity TCRs provide sufficient initial activation for tumor lysis without triggering the exhaustion pathway, thereby extending the functional duration of T cells.
3Measurement precision
If TCR affinity is enhanced to target mesothelin, then antigen-specific recognition is improved, but off-tumor recognition increases
Solution Approach 1:
The patent applies parameter changes by optimizing the binding affinity parameter (KD) of the TCR-mesothelin interaction. The TCRs are designed with intermediate affinity to specifically recognize mesothelin on tumor cells while avoiding cross-reactivity with similar but non-critical self-proteins. This precise control of affinity parameters achieves specific recognition without off-tumor effects.
Data Source
AI summary
Mesothelin-specific binding proteins including mesothelin-specific T cell receptor (TCR) that specifically binds to mesothelin including. for example. in a complex with an MHC. Methods of making and using the mesothelin-specific binding proteins are also described, including the use of the mesothelin-specific binding protein in adoptive cell therapy.