Stabilized MHC Complexes for High-Throughput TCR Screening

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for high-throughput screening of TCR-binding peptide ligand/MHC molecule complexes face challenges in stability, specificity, and efficiency, particularly in generating high-quality pMHC complexes for clinical and research applications.

Innovation Solution

A method involving the use of suitably stabilized MHC I molecules, specifically HLA-A proteins with artificially introduced covalent bridges between amino acids in the alpha1 domain, to form stable peptide-MHC complexes that can be screened for TCR-binding.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional MHC molecules are used for high-throughput screening, then the screening process can be performed, but the complexes lack stability and specificity leading to poor screening quality

Engineering Contradiction:

Improvestability of pMHC complexesVSAvoidthroughput of screening

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent introduces covalent bridges between the alpha1 and alpha2 helices of the MHC molecule, fundamentally changing the structural parameter of the MHC complex. This modification stabilizes the MHC molecule in its folded state, enabling it to maintain stable peptide-MHC complexes during high-throughput screening without requiring continuous peptide binding, thus resolving the contradiction between stability and throughput.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If peptide-MHC complexes are generated for TCR binding screening, then TCR ligands can be identified, but the complexes lack specificity and affinity

Engineering Contradiction:

Improvespecificity of TCR binding detectionVSAvoidcomplexity of complex generation

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent performs preliminary stabilization of the MHC molecule by introducing covalent bridges between the alpha1 and alpha2 helices before peptide binding. This preliminary structural stabilization ensures that the MHC molecule maintains its folded conformation and presents peptides with high specificity and affinity, enabling accurate TCR binding detection without requiring complex generation procedures.

Inventive Principle:

Principle #10Preliminary action

3Manufacturing precision

If high-quality pMHC complexes are generated for TCR binding, then specific TCR ligands can be identified, but the process is time-consuming and low throughput

Engineering Contradiction:

Improvequality of pMHC complexesVSAvoidtime required for complex generation

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The stabilized MHC molecule with covalent bridges between alpha1 and alpha2 helices is capable of self-maintaining its folded structure without requiring external stabilization agents or complex generation procedures. This self-service capability allows the MHC molecule to rapidly bind peptides and form high-quality complexes immediately, eliminating time-consuming stabilization steps and enabling high-throughput screening.

Inventive Principle:

Principle #25Self-service

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

The stabilized MHC molecules enable the generation of high-affinity, stable pMHC complexes that are recognized by TCRs with high specificity and selectivity, facilitating efficient high-throughput screening and potential applications in cancer immunotherapy.

Implementation Method 1

suitably stabilized MHC I molecules, specifically HLA-A proteins with artificially introduced covalent bridges between amino acids in the alpha1 domain

Methodology Applied

Scientific EffectCovalent bonding: Chemical Bonding

Implementation Method 2

contacting said suitably stabilized MHC I molecule with a multitude of peptide ligands thereof, to form peptide ligand/MHC (pMHC) molecule complexes

Methodology Applied

Scientific EffectProtein-protein interaction:

Implementation Method 3

screening said pMHC molecule complexes for TCR-binding

Methodology Applied

Scientific EffectReceptor-ligand interaction:

Data Source

PatentEP3850363B1Method for high throughput peptide-MHC affinity screening for TCR ligands by stabilised, peptide-free MHC complexes

Publication Date: 2025.01.22 IMMATICS BIOTECHNOLOGIES GMBH

Figure 1a~1b
Figure 2a~2d
Figure 3a~3d

AI summary

- 80 -Abstract The present invention relates to a method for high throughput screening for a TCR- binding peptide ligand/MHC molecule complex, comprising a stabilized peptide-MHC molecule and respective uses of said method. The present invention further relates to polypeptides comprising or consisting of stabilized MHC molecules or peptide binding fragments thereof, pharmaceutical compositions comprising said polypeptides, vaccines comprising said pharmaceutical composition and uses of said vaccine for the manufacturing of a medicament and/or in the prevention of cancer The present invention further relates to nucleic acids encoding said polypeptides and vectors comprising said nucleic acids.