Engineered T Cell Receptors for Multi-Allele Tumor Targeting
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Solution Overview
Problem
Current TCR-based therapies for treating EBV-associated diseases and cancers are limited by restricted MHC-I allele specificity, particularly to HLA-A*02:01, and lack of comprehensive TCR sequences for diverse antigen recognition, which hampers effective treatment of individuals who do not express this allele and solid tumors.
Innovation Solution
Development of novel TCRs with improved antigen specificity, binding properties, and stability, specifically targeting EBV-derived peptides, mutant splice-factor-induced peptides of MAPK8IP2, and HERV-K gag protein peptides, by inserting heterologous TCRs into the genome of T cells, enabling diverse antigen recognition and cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional TCR-based therapies targeting HLA-A*02:01 restricted peptides are used, then effective treatment is achieved for individuals with this allele, but treatment is ineffective for individuals who do not express HLA-A*02:01 allele
Solution Approach 1:
The patent develops TCRs that can recognize multiple MHC-I alleles beyond HLA-A*02:01, including HLA-B*07:02, HLA-C*07:01, and others. This multi-allele recognition capability makes the TCR therapy universally applicable to diverse patient populations regardless of their specific MHC-I genotype, resolving the contradiction between treatment efficacy and adaptability.
Solution Approach 2:
The patent employs TCRs with modified amino acid sequences in the CDR regions, particularly CDR3, to alter antigen binding properties. By changing specific amino acid residues in the TCR variable regions, the therapy achieves broad recognition across different MHC-I alleles while maintaining stable binding, thus improving both reliability and versatility simultaneously.
2Measurement precision
If TCRs with high antigen specificity are designed, then precise targeting of cancer cells is achieved, but the TCR may fail to recognize variants of the antigen
Solution Approach 1:
The patent focuses modifications on specific local regions of the TCR, particularly the CDR3 loops of both α and β chains, while maintaining the overall TCR structure. By optimizing amino acid sequences in these local binding regions, the TCR achieves high precision for specific peptide-MHC complexes while retaining flexibility to recognize antigen variants through subtle binding adjustments.
Solution Approach 2:
The patent creates composite TCR structures combining specific amino acid sequences in CDR1, CDR2, and CDR3 regions that work synergistically. The composite design integrates multiple contact points that collectively provide both high specificity for the primary antigen and adaptability to recognize variant peptides through alternative binding modes.
3Reliability
If synthetic TCRs are engineered to recognize tumor-specific antigens, then targeted cytotoxicity against cancer cells is achieved, but the procedure becomes complicated and applicable only to limited cancer types
Solution Approach 1:
The patent uses naturally occurring TCR sequences from tumor-infiltrating lymphocytes that have already been proven effective against specific cancers. By copying and engineering these pre-validated TCRs rather than designing de novo TCRs, the therapy achieves reliable tumor cell killing while simplifying the development process and reducing procedural complexity.
Solution Approach 2:
The patent divides the TCR engineering approach into modular components: selecting target antigens based on cancer type, engineering specific TCR sequences for each antigen-MHC combination, and applying appropriate delivery methods. This segmentation allows the therapy to be systematically adapted to different cancer types without requiring complete procedural redesign, reducing overall complexity.
Data Source
AI summary
The present application describes T cell receptors specifically binding tumor antigen derived peptides, especially derived from Mitogen-Activated Protein Kinase 8 Interacting Protein 2 (MAPK8IP2), Epstein-Barr Virus (EBV) proteins or Human Endogenous Retrovirus (HERV), as well as engineered T cells expressing these receptors, nucleic acids encoding these T cell receptors and methods of using T cells expressing these engineered T cells in adoptive cell transfer to treat diseases in a subject.