Bioorthogonal T Cell Receptor Interfaces for Stable Specific Binding

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Solution Overview

Problem

Existing T-cell receptor (TCR) drugs face challenges due to weak affinity and cross-reactive properties, limiting their effectiveness in cancer treatment.

Innovation Solution

Development of synthetic TCR molecules with bioorthogonal interfaces, featuring amino acid substitutions that enhance the selective binding between TCR alpha and beta chains, allowing for improved stability and specificity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional TCR molecules are used, then the basic recognition function is maintained, but the affinity is weak and cross-reactivity occurs

Engineering Contradiction:

Improvebinding affinityVSAvoidcross-reactivity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by introducing bioorthogonal interfaces through specific amino acid substitutions at defined positions in the TCR alpha and beta chains. These substitutions modify the binding interface parameters to achieve high-affinity, specific interactions that eliminate cross-reactivity while maintaining antigen recognition function.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs asymmetry by creating non-symmetric bioorthogonal interfaces through strategically placed amino acid substitutions at different positions (e.g., position 124, 126, 128, 130, 132, 134, 138, 140, 142, 144, 145, 158, 161, 163, 168, 171, 172, 173, 175, 177, 179, 181, 183, 205, 207 in the alpha chain and corresponding positions in the beta chain). This asymmetric design ensures specific pairing between alpha and beta chains while preventing cross-reactivity.

Inventive Principle:

Principle #4Asymmetry

2Reliability

If TCR molecules are engineered for higher affinity, then binding specificity improves, but structural stability may be compromised

Engineering Contradiction:

Improvebinding specificityVSAvoidmolecular stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent uses parameter changes to simultaneously achieve high binding specificity and molecular stability by introducing bioorthogonal interfaces through controlled amino acid substitutions. The substitutions are designed to create complementary binding surfaces that provide both specific antigen recognition and stable intrachain interactions.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies composite materials by combining the variable domains (for antigen binding) with engineered constant domains featuring bioorthogonal interfaces. This composite structure integrates the functional specificity of natural TCR variable regions with the structural stability of engineered constant region interfaces.

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20260055158A1Bioorthogonal t cell receptor molecules and methods of making and using the same

Publication Date: 2026.02.26 THE UNIV OF NORTH CAROLINA AT CHAPEL HILL

AI summary

This invention relates synthetic T cell receptor molecules and methods of making and using the same.