High-Affinity TCR Mutations for SSX2 Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current T cell receptors (TCRs) have limited affinity for the KASEKIFYV-HLA A0201 complex, which hampers their effectiveness in targeting tumor cells, particularly in cancer therapies such as adoptive immunotherapy.
Innovation Solution
Development of a high-affinity TCR with specific mutations in the α and β chain variable domains, including CDR regions, to enhance binding affinity for the KASEKIFYV-HLA A0201 complex, achieving at least twice the affinity of wild-type TCRs.
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 binding affinity is limited and insufficient for effective tumor cell targeting
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the CDR regions of the TCR variable domains. The sequence optimizations at positions 31-33, 51-58, and 93-106 of the α chain and positions 27-31, 49-54, and 92-106 of the β chain directly alter the binding parameters, resulting in at least twice the affinity of wild-type TCRs for the KASEKIFYV-HLA A0201 complex
Solution Approach 2:
The patent applies local quality by making specific mutations only in the CDR regions (complementarity-determining regions) of the TCR variable domains while maintaining the overall structure. The mutations are localized to specific positions (e.g., 31-33, 51-58, 93-106 for α chain) that directly contact the antigen, enhancing binding affinity without compromising the overall TCR structure and function
2Duration of action of moving object
If TCR affinity for KASEKIFYV-HLA A0201 complex is increased through mutations, then the binding half-life is significantly improved, but the complexity of TCR structure increases
Solution Approach 1:
The patent uses parameter changes by introducing specific amino acid mutations in the CDR regions to extend the binding half-life. The mutations in positions 31-33, 51-58, and 93-106 of the α chain and positions 27-31, 49-54, and 92-106 of the β chain create stronger and more stable interactions with the KASEKIFYV-HLA A0201 complex, resulting in significantly improved binding half-life
Solution Approach 2:
The patent applies segmentation by dividing the TCR structure into distinct functional regions (α chain variable domain with CDR1, CDR2, CDR3 and β chain variable domain with CDR1, CDR2, CDR3) and optimizing each CDR region independently. This modular approach allows systematic improvement of binding half-life through targeted mutations in each CDR segment without requiring complete redesign of the entire TCR structure
Data Source
AI summary
Provided is a high-affinity T cell receptor (TCR) that recognizes SSX2, wherein the TCR has the property of binding to a KASEKIFYV (SEQ ID NO: 29)-HLA A0201 complex, and the binding affinity of the TCR to the KASEKIFYV (SEQ ID NO: 29)-HLA A0201 complex is at least twice the binding affinity of a wild-type TCR to the KASEKIFYV (SEQ ID NO: 29)-HLA A0201 complex. Also provided is a fusion molecule of such a TCR with a therapeutic agent. Such a TCR can be used alone or in combination with a therapeutic agent to target tumor cells presenting the KASEKIFYV (SEQ ID NO: 29)-HLA A0201 complex.