MHC Class II Single Chain Trimer for TCR Verification

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Solution Overview

Problem

Current pMHC-TCR pairing technologies face challenges in verifying predicted epitopes and efficiently identifying antigen-specific CD4+ T cells, particularly in the context of adoptive cell therapy where precise T cell receptor recognition is crucial.

Innovation Solution

Development of MHC Class II single chain trimer (SCT) proteins and associated assays that enable the discovery of multiple TCRs from multiple peptides, utilizing nucleic acid fragments encoding SCT proteins with specific subunits and linkers for modular assembly, allowing for the creation of stable multimers for antigen-specific T cell identification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional pMHC-TCR pairing technologies are used, then T cell receptor recognition can be achieved, but the verification of predicted epitopes and identification of antigen-specific CD4+ T cells remains inefficient and challenging

Engineering Contradiction:

ImproveTCR recognition accuracyVSAvoidEpitope verification efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The MHC class II molecule is segmented into separate alpha and beta chain components that can be independently manipulated and recombined. This segmentation allows for modular assembly of different MHC alleles with specific peptides, enabling systematic verification of multiple epitope-TCR pairs simultaneously rather than testing each combination individually

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates a universal platform using standardized linkers (L1, L2) and common structural elements that can accommodate multiple different MHC class II allele combinations and peptide variants. This multi-functional design allows a single assay system to verify numerous epitope predictions across different HLA alleles, dramatically increasing throughput while maintaining recognition accuracy

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If multiple MHC class II alleles are expressed to cover diverse HLA types, then broader T cell coverage is achieved, but the complexity of determining unique alpha/beta heterodimer combinations increases

Engineering Contradiction:

ImproveHLA allele coverageVSAvoidHeterodimer combination identification

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent extracts and separates the alpha and beta chain determination from the complex heterodimer identification problem. By using nucleic acid sequencing to directly identify the specific alpha and beta chain sequences in each SCT construct, the method eliminates the ambiguity of inferring heterodimer composition from phenotypic data alone, simplifying the process of tracking which specific allele combinations are expressed

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent implements a feedback mechanism where nucleic acid sequencing data from the SCT constructs provides direct information about the specific MHC alleles being expressed. This molecular feedback allows researchers to correlate T cell responses with precisely defined alpha/beta heterodimer combinations, enabling systematic deconvolution of which specific allele-peptide-TCR interactions are driving the immune response

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20230076204A1Single chain trimer MHC class ii nucleic acids and proteins and methods of use

Publication Date: 2023.03.09 INSTITUTE FOR SYSTEMS BIOLOGY

AI summary

Peptide-major histocompatibility (MHC) Class II nucleic acids and proteins are provided. Methods of their use, for example in methods of identifying antigen-specific T cells and adoptive cell therapy, are also provided.