Modified TCR Amino Acid Substitutions for Specificity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for enhancing T-cell receptor (TCR) binding affinity for cancer and infectious disease treatment often result in nonspecific binding and cross-reactivity, compromising specificity and safety.
Innovation Solution
A modified dual recognition DMF5 T-cell receptor with specific amino acid substitutions, including tyrosine at position 26 of the CDR2α chain and tryptophan at position 98 of the CDR2β chain, reduces off-target recognition and enhances specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR binding affinity is enhanced through random mutations or computational design, then the potency of immune response increases, but nonspecific binding and cross-reactivity increase
Solution Approach 1:
The patent applies local quality by making specific, localized amino acid substitutions at defined positions (e.g., position 50 of CDR2α, position 26 of CDR2α, position 98 of CDR2β) rather than random mutations throughout the TCR. This targeted approach modifies only the necessary local regions to achieve desired binding properties while preserving overall specificity.
Solution Approach 2:
The patent changes specific amino acid parameters at defined positions to optimize TCR function. By substituting specific residues (e.g., changing position 50 of CDR2α to certain amino acids while keeping position 26 as tyrosine and position 98 of CDR2β as tryptophan), the patent adjusts binding characteristics to achieve both high affinity and specificity.
2Reliability
If TCR affinity for pMHC is strengthened, then therapeutic potency increases, but cross-recognition of non-target antigens increases
Solution Approach 1:
The patent applies local quality by making specific, localized amino acid substitutions at defined positions (e.g., position 50 of CDR2α, position 26 of CDR2α, position 98 of CDR2β) rather than random mutations throughout the TCR. This targeted approach modifies only the necessary local regions to achieve desired binding properties while preserving overall specificity.
Solution Approach 2:
The patent changes specific amino acid parameters at defined positions to optimize TCR function. By substituting specific residues (e.g., changing position 50 of CDR2α to certain amino acids while keeping position 26 as tyrosine and position 98 of CDR2β as tryptophan), the patent adjusts binding characteristics to achieve both high affinity and specificity.
Data Source
Figure 1A~1B
Figure 2
Figure 3A~3B
AI summary
Molecular constructs and dual recognition constructs having a sequence encoding a TCR affinity weakening motif, and DNA and RNA sequences corresponding thereto, are presented. Modified T-cells and other cells transformed with the molecular contracts express a modified TCR that impart s a reduction, in non-specific binding, -an enhancement of binding specificity and an enhancement of binding affinity for a target antigen, compared to non-transformed ( wild-type, native) T-cells, are described. The modified TCRs possess an affinity enhancing motif and an affinity weakening motif. Methods of transforming cells and methods of using enriched populations of transformed cells, in the treatment of cancer and infections arid T-cell mediated pathologies are provided. The affinity weakening motif imparts a weakened interaction, of a TCR with major histocompatibility complex proteins, such as HLA proteins in humans. Soluble modified TCRs are also provided, Therapeutic preparations comprising modified T-cells, modified TCRs, and modified TCR-therapeutic agent-conjugates, are also provided.