Modified T-Cell Receptors for Covalent Peptide-MHC Binding

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Solution Overview

Problem

Current TCR gene therapy faces challenges in achieving long-lasting binding events between TCR and peptide-MHC complexes for effective T cell stimulation, particularly with low-abundance peptides failing to stimulate T cells effectively.

Innovation Solution

Formation of a covalent linkage, specifically a disulphide bond, between the TCR complementarity-determining region (CDR) and a peptide bound to an MHC protein by introducing a cysteine residue in the CDR to form a disulphide bond with a cysteine in the peptide.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If conventional non-covalent binding is used between TCR and peptide-MHC, then T cell activation can occur, but the binding duration is insufficient for effective stimulation

Engineering Contradiction:

Improvebinding durationVSAvoidstimulation effectiveness

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent changes the binding mechanism from non-covalent to covalent by introducing a disulphide bond between the TCR CDR and peptide-MHC. This fundamental parameter change in bond type transforms the transient interaction into a stable, long-lasting covalent linkage, directly resolving the contradiction between binding duration and stimulation effectiveness

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite binding system where the TCR is chemically linked to the peptide-MHC complex through a disulphide bond. This composite structure combines the antigen recognition function of TCR with the stable covalent bonding capability, resulting in a hybrid molecule that maintains both specificity and prolonged binding

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If low-abundance peptides are used as targets, then therapy specificity can be improved, but T cell stimulation fails due to insufficient binding events

Engineering Contradiction:

Improvepeptide target rangeVSAvoidstimulation frequency

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent fundamentally changes the binding parameter from weak non-covalent interactions to strong covalent disulphide bonds. This parameter change enables T cells to effectively bind and be stimulated by low-abundance peptides that would otherwise produce insufficient binding events, thereby expanding the range of viable peptide targets while maintaining stimulation frequency

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Enhances T cell stimulation by prolonging the duration of TCR-peptide-MHC interactions, improving the effectiveness of T cell-based therapies for conditions like cancer and autoimmune diseases.

Implementation Method 1

Methodology Applied

Scientific EffectDisulphide bond formation: Chemical Bonding

Data Source

PatentUS20250270280A1Modified binding proteins and therapeutic uses thereof

Publication Date: 2025.08.28 MONASH UNIV

AI summary

The present invention relates to modified T cell receptors and their uses in treating various diseases or conditions, particularly cancer and autoimmune diseases. A binding protein comprising a variable domain comprising a complementarity-determining region (CDR) capable of contacting a peptide bound to an HLA molecule, wherein the CDR 5 comprises a cysteine capable of forming a disulphide bond with a cysteine in the peptide bound to the HLA molecule, typically wherein the cysteine is introduced into the CDR by mutation or modification of an existing residue.