TCR Specificity for MAGE-B2 Peptide via CDR Engineering
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Solution Overview
Problem
Current T cell receptors (TCRs) face challenges in selectively binding to specific cancer-associated antigens like MAGE B2 while avoiding cross-reactivity with similar antigens, such as MAGE A4, which limits their therapeutic efficacy in cancer immunotherapy.
Innovation Solution
Development of TCRs with specific alpha and beta chain variable domains that exhibit high affinity and selectivity for the MAGE B2 peptide GVYDGEEHSV bound to HLA-A*0201, forming contacts with residues V2, Y3, and D4, while minimizing binding to the MAGE A4 peptide GVYDGREHTV, thereby enhancing targeted delivery of therapeutic agents to cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCRs are designed to bind with high affinity to MAGE B2 peptide-HLA-A*0201 complex, then therapeutic efficacy against melanoma is improved, but cross-reactivity with similar antigens like MAGE A4 increases causing off-target effects
Solution Approach 1:
The patent applies local quality by engineering specific amino acid substitutions in the TCR variable domains (particularly in CDR regions) that create localized binding pocket characteristics. These local modifications at specific residue positions enable the TCR to distinguish between MAGE B2 and MAGE A4 peptides by forming favorable interactions with unique features of the MAGE B2 peptide sequence (residues 230-239), thereby achieving high affinity binding to the target antigen while maintaining selectivity against cross-reactivity with similar antigens.
2Manufacturing precision
If TCR variable domains are engineered to form specific contacts with MAGE B2 residues V2, Y3, and D4, then binding specificity is improved, but TCR structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the TCR into distinct functional modules: variable domains (Vα and Vβ) that provide antigen recognition specificity, and constant domains that provide structural stability. Within the variable domains, the complementarity determining regions (CDR1, CDR2, CDR3) are further segmented as independent functional units that can be separately engineered. This modular segmentation allows systematic optimization of binding specificity through targeted amino acid substitutions in specific CDR loops while maintaining overall TCR structural integrity and foldability.
Solution Approach 2:
The patent applies parameter changes by systematically modifying amino acid parameters (sequence composition, charge distribution, hydrophobicity) in the TCR variable domains. Specific amino acid substitutions are introduced to alter the chemical properties of the binding pocket, enabling formation of favorable interactions with MAGE B2 residues V2, Y3, and D4. These parameter changes include introducing charged residues for electrostatic interactions, hydrophobic residues for van der Waals contacts, and hydrogen bonding capabilities, thereby achieving enhanced binding specificity through controlled modification of molecular interaction parameters.
Data Source
AI summary
The present invention relates to T cell receptors (TCRs) which bind the HLA-A*0201 restricted peptide GVYDGEEHSV (SEQ ID NO: 1) derived from the MAGE-B2 protein. The TCRs of the invention demonstrate excellent specificity profiles for this MAGE epitope. Also provided are nucleic acids encoding the TCRs, cells engineered to present the TCRs, cells harbouring expression vectors encoding the TCRs and pharmaceutical compositions comprising the TCRs, nucleic acids or cells of the invention.