High-Affinity TCR for SSX2 Antigen Recognition
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Solution Overview
Problem
Current T cell receptors (TCRs) have limited affinity for the KASEKIFYV-HLA A0201 complex, which hampers their effectiveness in targeting and treating tumors expressing the SSX2 protein-derived antigen.
Innovation Solution
Development of a TCR with enhanced affinity for the KASEKIFYV-HLA A0201 complex by mutating specific residues in the CDR regions of the TCR α and β chain variable domains, resulting in a receptor with significantly improved binding characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TCR is used, then the TCR can recognize the KASEKIFYV-HLA A0201 complex, but the affinity is limited and binding duration is short
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the CDR regions of the TCR α and β chains. These mutations alter the biochemical parameters of the TCR antigen-binding site, including charge distribution, hydrophobicity, and steric configuration, to enhance complementarity with the KASEKIFYV-HLA A0201 complex. This results in significantly improved binding affinity and extended binding half-life compared to wild-type TCR.
2Reliability
If TCR affinity for tumor antigen is increased, then the TCR can target tumor cells more effectively, but the complexity of developing and characterizing the TCR increases
Solution Approach 1:
The patent applies local quality by focusing mutations specifically on the CDR (complementarity-determining region) residues that directly contact the antigen, rather than modifying the entire TCR molecule. This localized approach allows for precise optimization of antigen binding while maintaining the overall structural integrity and function of the TCR. The method systematically evaluates specific position mutations to achieve high affinity without excessive complexity.
Data Source
AI summary
Provided is a T-cell receptor (TCR) having the characteristic of binding to a KASEKIFYV-HLA A0201 complex, wherein the binding affinity of the TCR to the KASEKIFYV-HLA A0201 complex is at least two times that of a wild-type TCR to the KASEKIFYV-HLA A0201 complex. The TCR may be used alone or in combination with a therapeutic agent, so as to target tumor cells presenting the KASEKIFYV-HLA A0201 complex.