Engineered T Cell Receptors for High Affinity PRAME Targeting
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Solution Overview
Problem
Current T cell receptors (TCRs) have low affinity for cancer-specific antigens, making it difficult to effectively target and destroy cancer cells, and increasing affinity while maintaining specificity is challenging due to the inherent degeneracy of TCR antigen recognition, leading to potential off-target binding and clinical toxicity.
Innovation Solution
Engineered TCRs with specific mutations in the alpha and beta chain variable domains that bind to the SLLQHLIGL-HLA-A*02 complex with high affinity and specificity, enhancing their ability to recognize and target PRAME-positive cancer cells while minimizing cross-reactivity with healthy cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR affinity for cancer-specific antigens is increased through engineering mutations, then the ability to target and destroy cancer cells is improved, but the risk of off-target binding and clinical toxicity increases
Solution Approach 1:
The patent applies local quality by making specific mutations only in the CDR3 regions of the TCR alpha and beta chains, which are the complementarity determining regions directly involved in antigen recognition. This localized modification approach allows affinity enhancement precisely where needed (in the antigen-binding interface) while leaving the rest of the TCR structure unchanged, thereby minimizing the risk of unintended off-target effects throughout the molecule.
Solution Approach 2:
The patent employs parameter changes by systematically mutating amino acid residues at specific positions within the CDR3 regions to optimize binding affinity. Through rational design and screening of mutant libraries, the patent identifies specific parameter changes (amino acid substitutions) that enhance cancer cell targeting while maintaining specificity, resolving the contradiction between improved efficacy and reduced toxicity.
2Productivity
If TCR affinity for cancer-specific antigens is increased, then therapeutic effectiveness is improved, but the degeneracy of TCR antigen recognition leads to potential off-target binding
Solution Approach 1:
The patent applies segmentation by dividing the TCR into distinct functional regions (CDR1, CDR2, and CDR3) and focusing mutations specifically on the CDR3 regions, which are the most variable and antigen-contacting portions. This segmentation allows independent optimization of affinity in the CDR3 regions while preserving the specificity-determining framework regions and other CDRs unchanged.
Solution Approach 2:
The patent makes specific amino acid substitutions only at selected positions within the CDR3 regions rather than throughout the entire TCR sequence. This localized mutation strategy enhances binding productivity at the antigen interface while maintaining the overall specificity profile determined by the unchanged framework regions and other CDRs.
3Reliability
If natural TCR affinity is used, then specificity is maintained, but the low affinity makes it difficult to effectively target and destroy cancer cells
Solution Approach 1:
The patent applies parameter changes by introducing targeted amino acid substitutions in the CDR3 regions to increase binding affinity from low (natural) to high (engineered). These controlled parameter changes in specific positions allow the TCR to overcome the naturally low affinity limitation while the patent's screening and validation processes ensure that specificity is maintained through careful selection of mutations.
Solution Approach 2:
The patent performs preliminary action by conducting in vitro screening and characterization of mutant TCRs before clinical application. This preliminary testing allows identification of mutants with both high affinity and maintained specificity, resolving the contradiction between improved productivity and preserved reliability before therapeutic use.
Data Source
AI summary
The present invention relates to T cell receptors (TCRs) that bind the HLA-A*02 restricted peptide SLLQHLIGL (SEQ ID NO: 1) derived from the germline cancer antigen PRAME. Said TCRs may comprise non-natural mutations within the alpha and/or beta variable domains relative to a native PRAME TCR. The TCRs of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of malignant disease.