High-Affinity TCR Mutations for AFP-Positive Liver Cancer
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Solution Overview
Problem
Current T-cell receptors (TCRs) have limited affinity and binding duration for the KWVESIFLIF-HLA A2402 complex, which hampers their effectiveness in targeting tumor cells, particularly in liver cancer treatment.
Innovation Solution
Development of a high-affinity TCR with modified α and β chain variable domains, featuring specific mutations in complementarity-determining regions (CDRs), which enhances binding affinity and stability, allowing for prolonged interaction with the KWVESIFLIF-HLA A2402 complex.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TCR is used, then the TCR can recognize the KWVESIFLIF-HLA A2402 complex, but the binding affinity and binding duration are limited
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations in the CDR regions of the TCR α and β chains. These mutations (such as H92G, F93W, G94Y/Q/K/D/A/H/I/L/M/N/R/T, D95R/G/N in α chain and S94A, L95S, Q97V, K100R, D101M/G, E102Q/T, Q103E/L in β chain) modify the binding parameters of the TCR to achieve at least twice the binding affinity and extended binding half-life compared to wild-type TCRs
Solution Approach 2:
The patent applies local quality by making specific mutations only in the complementarity-determining regions (CDRs) of the TCR variable domains, while keeping the framework regions intact. This localized modification approach allows the TCR to maintain its overall structure while enhancing the binding interface properties specifically where it interacts with the KWVESIFLIF-HLA A2402 complex
2Reliability
If TCR affinity is increased through mutations, then the binding affinity and stability are enhanced, but the TCR structure and complexity increase
Solution Approach 1:
The patent systematically modifies specific amino acid parameters in the CDR regions to enhance binding stability. The mutations are carefully selected to improve binding affinity without causing structural collapse, achieving at least twice the binding affinity while maintaining TCR structural integrity through controlled parameter changes in the variable domains
3Productivity
If the TCR is designed for high affinity binding, then the targeting effectiveness is improved, but the manufacturing and screening difficulty increases
Solution Approach 1:
The patent focuses mutations specifically in the CDR regions (local quality) rather than throughout the entire TCR sequence, which simplifies the manufacturing process. The framework regions remain unchanged and can be produced using standard protocols, while only the variable domain CDRs require specialized mutagenesis and screening, thereby reducing overall manufacturing complexity
Solution Approach 2:
The patent defines specific amino acid substitutions at predetermined positions in the CDR regions, which standardizes the manufacturing process. By specifying exact mutation sites and allowable amino acid options, the patent enables more consistent and reproducible production of high-affinity TCRs compared to random mutagenesis approaches
Data Source
AI summary
Provided is a T-cell receptor (TCR) that can bind to a KWVESIFLIF (SEQ ID NO: 38)-HLA A2402 complex, wherein the binding affinity thereof is at least 2 times that of a wild-type TCR. Further provided is a fusion molecule of the TCR with a therapeutic agent, which fusion molecule targets a tumor cell presenting the KWVESIFLIF (SEQ ID NO: 38)-HLA A2402 complex.