High-Affinity TCR Engineering for AFP Tumor Targeting
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Solution Overview
Problem
Existing T cell receptors (TCRs) have limited affinity for the FMNKFIYEI-HLA A0201 complex, which hampers their effectiveness in targeting tumor cells, particularly in AFP-related diseases such as hepatocellular carcinoma.
Innovation Solution
A TCR with enhanced affinity for the FMNKFIYEI-HLA A0201 complex is developed by mutating the CDR regions of its α chain variable domain, specifically CDR1α, CDR2α, and CDR3α, and optionally introducing an artificial inter-chain disulfide bond, resulting in a binding affinity at least 5-fold greater than wild-type TCRs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TCR is used, then the TCR can recognize AFP antigen, but the binding affinity is limited and insufficient for effective tumor targeting
Solution Approach 1:
The patent applies parameter changes by mutating the CDR regions of the TCR α-chain variable domain to alter the binding interface properties. Specifically, amino acid substitutions in CDR1α, CDR2α, and CDR3α regions modify the chemical and physical characteristics of the antigen-binding site, enabling enhanced affinity for the FMNKFIYEI-HLA A0201 complex while maintaining specific recognition.
Solution Approach 2:
The patent implements local quality by introducing an artificial inter-chain disulfide bond between the α-chain and β-chain of the TCR. This localized structural modification stabilizes the TCR configuration at the binding interface, thereby enhancing binding affinity without affecting the overall TCR structure or antigen specificity.
2Reliability
If CDR regions are mutated to enhance affinity, then binding strength increases, but structural stability may be compromised
Solution Approach 1:
The patent simultaneously optimizes multiple parameters by coordinating CDR region mutations with the introduction of an artificial disulfide bond. The CDR mutations enhance affinity by modifying binding interface parameters, while the disulfide bond compensates for potential structural instability by strengthening the inter-chain linkage, thus achieving both high affinity and structural stability.
3Reliability
If artificial inter-chain disulfide bond is introduced, then TCR stability and affinity are enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent achieves enhanced binding affinity through parameter changes in the CDR regions and the introduction of an artificial disulfide bond. While these modifications do increase manufacturing complexity, the patent provides specific sequence information and structural guidelines that facilitate the production process, balancing the trade-off between performance enhancement and manufacturing feasibility.
Data Source
AI summary
Provided in the present invention is a T-cell receptor (TCR) having the characteristic of binding a FMNKFIYEI-HLA A0201 complex. The binding affinity of the TCR to the FMNKFIYEI-HLA A0201 complex is at least 5 times that of a wild-type TCR to the FMNKFIYEI-HLA A0201 complex. Further provided in the present invention is a fusion molecule of the TCR with a therapeutic agent. The TCR may be used alone or in combination with the therapeutic agent, so as to target a tumor cell presenting the FMNKFIYEI-HLA A0201 complex.