Modified TCRs with Interchain Disulfide Bonds
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Solution Overview
Problem
Current methods for introducing T cell receptors (TCRs) specific for cancer-specific MHC-peptide complexes into T cells for immunotherapy face challenges, such as requiring high concentrations of peptide pulsing and potential mismatched TCR pairs leading to reduced efficacy.
Innovation Solution
Development of T cells expressing TCRs with an interchain disulfide bond between extracellular constant domain residues, which are not present in native TCRs, to enhance specificity and affinity for peptide-MHC or CD1-antigen complexes, and the use of single-chain TCRs to avoid mismatched pairs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native TCRs are used for immunotherapy, then T cells can recognize MHC-peptide complexes, but high concentrations of peptide pulsing are required and mismatched TCR pairs reduce efficacy
Solution Approach 1:
The patent introduces non-native disulfide bonds at specific positions in the TCR constant domains to stabilize the TCR structure and enhance its binding affinity for pMHC complexes. This structural modification changes the physical-chemical parameters of the TCR, allowing it to function effectively at lower peptide concentrations and reducing the requirement for high-dose peptide pulsing during in vitro activation.
Solution Approach 2:
The patent creates a hybrid TCR structure by combining native TCR variable regions (which provide antigen specificity) with modified constant regions containing non-native disulfide bonds (which provide structural stability). This composite approach merges the advantages of natural antigen recognition with engineered structural reinforcement, improving overall TCR performance without losing specificity.
2Reliability
If native TCRs are used for immunotherapy, then T cells can recognize antigen, but mismatched TCR pairs lead to reduced efficacy
Solution Approach 1:
The patent uses a common heterologous constant domain (such as human TRAC and TRBC2) as an intermediary structure that both the alpha and beta chains of the TCR can associate with. This standardized constant region acts as a mediator that facilitates proper pairing between the variable regions of the alpha and beta chains, ensuring that the correct TCR heterodimers are formed and reducing mismatches that would otherwise reduce therapeutic efficacy.
3Adaptability or versatility
If TCRs are introduced into T cells for immunotherapy, then cancer-specific targeting is achieved, but the complexity of TCR engineering and validation increases
Solution Approach 1:
The patent divides the TCR engineering process into distinct modular components: (1) selection of antigen-specific variable regions, (2) incorporation of standardized constant domains with defined disulfide bond positions, and (3) assembly into complete TCR alpha and beta chains. This segmentation allows each module to be independently optimized and validated, simplifying the overall engineering process while maintaining the ability to target multiple different cancer antigens by simply changing the variable region components.
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 modified TCRs exhibit improved binding affinity and specificity, potentially leading to more effective targeting and recognition of cancer cells, enhancing the efficacy of T cell adoptive immunotherapy.
Implementation Method 1
said TCR comprising an interchain disulfide bond between extracellular constant domain residues which is not present in native TCRs
Data Source
AI summary
This invention provides a cell presenting at least one T cell receptor (TCR) anchored to the membrane by a transmembrane sequence, said TCR comprising an interchain disulfide bond between extracellular constant domain residues which is not present in native TCRs.