Engineered Murine TCRs for HCC Targeting
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Solution Overview
Problem
Current immunotherapies for hepatocellular carcinoma (HCC) face challenges due to the variability of tumor-associated antigens (TAAs) expression and the limited efficacy of existing T cell receptors (TCRs) specific for the hAFP158 epitope, which often result in tumor immune escape and off-target toxicity.
Innovation Solution
Development of engineered murine T cell receptors (mTCRs) with high sequence identity to specific polypeptides that recognize the hAFP158 epitope, designed to enhance the affinity and specificity of T cells for HCC tumor cells, thereby improving antitumor efficacy while minimizing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild type human TCR specific for hAFP158 epitope is used, then the TCR can recognize the epitope, but the antitumor effect is weak or no effector function is produced
Solution Approach 1:
The patent applies parameter changes by mutating the CDR regions of the wild type human TCR to increase affinity for the hAFP158 epitope. Specific amino acid substitutions were made in the CDR1, CDR2, and CDR3 regions of both α and β chains, transforming the low-affinity wild type TCR into high-affinity engineered TCRs that effectively recognize and kill HCC tumor cells.
2Reliability
If high affinity TCR-T cells are engineered to increase recognition of HCC tumor cells, then antitumor efficacy may be improved, but severe off-target toxicity occurs
Solution Approach 1:
The patent applies local quality by making targeted mutations only in the CDR regions responsible for epitope recognition, while preserving the overall TCR structure and specificity. This localized modification approach enhances affinity for the desired target (hAFP158) while maintaining selectivity, thereby improving antitumor efficacy without proportionally increasing off-target toxicity.
3Reliability
If TCRs are engineered to increase the chance of finding optimal TCRs with high antitumor efficacy, then more TCR variants are needed, but the complexity of identifying and testing increases
Solution Approach 1:
The patent applies segmentation by dividing the TCR into functional modules (CDR1, CDR2, CDR3 regions of α and β chains) and independently optimizing each segment through targeted mutations. This modular approach allows systematic evaluation of different CDR combinations to identify optimal TCR variants with high antitumor efficacy, reducing the complexity of the overall identification process.
Data Source
AI summary
T cell receptors that specifically recognize hAFP158 and methods of their use are provided.