MAGE-A3 Specific T Cell Receptor Engineering for Reduced Titin Cross-Reactivity

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Solution Overview

Problem

Current T cell receptors (TCRs) specific for MAGE-A3 often exhibit cross-reactivity with healthy tissue epitopes, leading to severe side effects due to binding with titin-derived epitopes, necessitating the development of TCRs with reduced or no cross-reactivity to effectively target cancer cells while minimizing harm to healthy tissues.

Innovation Solution

Design and isolation of TCRs with specific amino acid sequences for the MAGE-A3 epitope, ensuring minimal to no recognition of titin-derived epitopes, and potentially other MAGE-A family members, through precise engineering of CDR regions and modifications to enhance specificity and reduce immunogenicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a TCR is designed to target MAGE-A3 with high affinity, then cancer cell recognition is improved, but cross-reactivity with titin-derived epitopes increases causing severe side effects

Engineering Contradiction:

ImproveMAGE-A3 recognition specificityVSAvoidcross-reactivity with titin epitope

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by focusing modifications on specific local regions (CDR loops) of the TCR while maintaining the overall structure. By precisely altering the amino acid sequences in the complementarity determining regions, the TCR achieves high specificity for MAGE-A3 while avoiding cross-reactivity with titin, thus resolving the contradiction between affinity and harmful cross-reactivity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the molecular parameters (amino acid sequences) of the TCR to achieve the desired specificity. By modifying the CDR regions' amino acid composition and structure, the TCR's binding characteristics are altered to recognize MAGE-A3 with high affinity while eliminating cross-reactivity with harmful epitopes

Inventive Principle:

Principle #35Parameter changes

2Productivity

If TCR affinity for MAGE-A3 is enhanced, then tumor targeting efficiency is improved, but immunogenicity and cross-reactivity with healthy tissue increase

Engineering Contradiction:

Improvetumor targeting efficiencyVSAvoidimmunogenicity and cross-reactivity

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent segments the TCR into functional regions (CDR1, CDR2, CDR3) and applies selective modifications to each segment. This segmentation allows independent optimization of each region's contribution to specificity and affinity, enabling high tumor targeting efficiency while minimizing harmful cross-reactivity through precise local adjustments

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20230340064A1MAGE-a3 specific t cell receptors and their use

Publication Date: 2023.10.26 MEDIGENE IMMUNOTHERAPIES GMBH

AI summary

The present invention relates to an isolated T cell receptor (TCR) specific for a MAGE-A3-derived peptide and to a polypeptide comprising a functional portion of the TCR. Further implicated are a multivalent TCR complex, a nucleic acid sequence encoding a TCR, a cell expressing the TCR and a pharmaceutical composition comprising the TCR. The invention also refers to the TCR for use as a medicament, in particular to the TCR for use in the treatment of cancer.