Engineered T Cell Receptors for AFP158 Binding
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Solution Overview
Problem
Current treatments for hepatocellular carcinoma, particularly in advanced stages, are limited, and there is a need for novel immunotherapeutic interventions that can specifically target the HLA-A2 restricted AFP158 peptide epitope.
Innovation Solution
Development of non-naturally occurring, purified, and engineered T cell receptors (TCRs) that bind specifically to the FMNKFIYEI (158-166) HLA-A2 complex, comprising TCR alpha and beta chain variable domains with defined amino acid sequences and mutations to enhance binding affinity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional T cell clones are used against AFP158, then some binding capability is achieved, but the binding affinity and specificity are insufficient for effective therapeutic intervention
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid sequences in the TCR variable domains (particularly CDR regions) to optimize binding affinity. Specific mutations are introduced at key positions to enhance interactions with the peptide-MHC complex, transforming the TCR from moderate to high affinity binder while maintaining antigen specificity.
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions specifically in the complementarity determining regions (CDR1, CDR2, CDR3) of the TCR variable domains. These localized changes concentrate the affinity-enhancing effects in the antigen-binding interface while leaving other functional regions intact, thereby improving binding without compromising overall TCR structure and function.
2Reliability
If TCR sequences are engineered to enhance binding affinity, then therapeutic efficacy is improved, but the risk of off-target binding and loss of specificity increases
Solution Approach 1:
The patent carefully selects amino acid substitutions that enhance affinity for the specific AFP158 peptide-MHC complex while avoiding changes that would broaden the binding spectrum. The mutations are chosen based on their ability to strengthen specific interactions with unique features of the target epitope, thereby maintaining specificity even as affinity increases.
Solution Approach 2:
The patent employs iterative selection and characterization of TCR variants to identify those with optimal balance between affinity and specificity. Through systematic evaluation of binding characteristics and cross-reactivity profiles, the invention selects TCR sequences that demonstrate high target specificity, using feedback from binding assays to guide further optimization and eliminate variants with off-target activity.
3Ease of manufacture
If natural TCR sequences are used, then the development process is simpler, but the binding characteristics are inadequate for effective cancer therapy
Solution Approach 1:
The patent applies preliminary action by pre-selecting and characterizing TCR sequences with promising binding characteristics before full therapeutic development. The invention identifies and validates engineered TCR variants with superior binding properties in advance, creating a optimized TCR repertoire that can be directly applied to therapeutic applications without requiring extensive further optimization during clinical development.
Data Source
AI summary
The present invention relates to T cell receptors (TCRs) which bind the HLA-A2 restricted FMNKFIYEI (158-166) SEQ ID NO: 1 peptide epitope derived from α Fetoprotein (AFP). Certain preferred TCRs of the invention demonstrate excellent binding characteristics and specificity profiles for this AFP epitope. T cell receptors of the invention may comprise at least one TCR alpha chain variable domain and/or at least one TCR beta chain variable domain, the alpha chain variable domain which may comprise an amino acid sequence that has at least 90% identity to the sequence of amino acid residues 1-112 of SEQ ID NO: 2, and/or the beta chain variable domain which may comprise an amino acid sequence that has at least 90% identity to the sequence of amino acid residues 1-112 of SEQ ID NO: 3.