NY-ESO-1 TCR Engineering for Specific Tumor Peptide Recognition

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Solution Overview

Problem

Existing T cell receptors (TCRs) targeting NY-ESO-1 antigens are immunogenic and cross-react with other peptides, leading to suboptimal affinity and immunological tolerance, limiting their effectiveness in cancer immunotherapy.

Innovation Solution

Development of TCRs with specific binding to the NY-ESO-1 peptide in the context of MHC (HLA-A2) that do not cross-react with off-target peptides, activating a T cell response two to four times greater than patient-derived TCRs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If patient-derived TCRs are used to target NY-ESO-1 antigens, then they can recognize the antigen in the context of MHC, but they exhibit immunogenicity and cross-react with other peptides, leading to suboptimal affinity and immunological tolerance

Engineering Contradiction:

Improvespecificity of TCR bindingVSAvoidimmunogenicity and cross-reactivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequences of TCR alpha and beta chains to optimize binding affinity and specificity. Through systematic variation of CDR regions and framework regions, the invention achieves TCRs with enhanced on-target binding while reducing off-target cross-reactivity and immunogenicity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates synthetic copies of patient-derived TCRs with optimized sequences. By copying the basic structure and antigen recognition capability while modifying specific amino acid residues, the invention produces TCRs that maintain antigen specificity but eliminate harmful immunogenicity and cross-reactivity

Inventive Principle:

Principle #26Copying

2Productivity

If TCRs are engineered to have high affinity for NY-ESO-1 peptide, then they can effectively activate T cell response, but they may cross-react with similar epitopes in the natural protein repertoire

Engineering Contradiction:

ImproveT cell activation responseVSAvoidfine specificity to peptide antigen

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions in the CDR3 regions of the TCR, which are the most critical for antigen recognition. By locally optimizing the binding interface while maintaining the overall TCR structure, the invention achieves high affinity for NY-ESO-1 without compromising specificity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs feedback through iterative screening and selection processes. TCR variants are tested for both affinity and specificity, and those showing cross-reactivity are eliminated. This feedback loop continues until TCRs are obtained that simultaneously achieve high productivity and fine specificity

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS12466870B2NY-ESO-1 T cell receptors and methods of use thereof

Publication Date: 2025.11.11 REGENERON PHARMACEUTICALS INC

AI summary

The present invention provides isolated T cell receptors (TCRs) that specifically bind to an HLA-displayed New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) peptides, as well as therapeutic and diagnostic methods of using those isolated TCRs.