MART-1 Epitope-Specific T Cell Receptor Affinity Optimization
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Solution Overview
Problem
Current T cell receptors specific to the MART-1 (27-35) epitope have limited clinical effectiveness due to low affinity for target cells expressing the MART-1 antigen, restricting their ability to recognize and kill tumor cells effectively.
Innovation Solution
Development of a MART-1 (27-35) epitope-specific T cell receptor comprising an α chain and a β chain with specific amino acid sequences and their variants, along with a nucleic acid molecule encoding these chains, which can be used to create a pharmaceutical composition or vector for treating melanoma, enhancing T cell recognition and affinity for the epitope.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TCR sequences are used, then the T cell receptor can recognize MART-1 epitope, but the affinity for target cells is low
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences of the TCR α and β chains to optimize binding affinity. Specifically, the patent identifies and selects TCR sequences with improved affinity parameters for the MART-1(27-35) epitope, demonstrating that changing sequence parameters can enhance binding strength while maintaining recognition capability.
2Reliability
If T cell affinity for MART-1 epitope is increased, then tumor cell recognition improves, but the complexity of obtaining high-affinity TCR increases
Solution Approach 1:
The patent applies preliminary action by pre-identifying and characterizing TCR sequences with high affinity for MART-1 epitope before clinical application. The patent performs preliminary screening and selection of TCR α and β chain sequences that have demonstrated high binding affinity, thereby simplifying the subsequent implementation process and reducing the complexity of obtaining high-affinity TCR for therapeutic use.
Data Source
AI summary
Provided is a MART-1 (27-35) epitope-specific T cell receptor, comprising an α chain and a β chain. The α chain comprises three complementary determining regions, respective sequences thereof being positions 61-66, positions 84-89, and positions 124-136 of SEQ ID No. 3. The β chain comprises three complementary determining regions, respective amino acid sequences thereof being positions 46-50, positions 68-73, and positions 112-125 of SEQ ID No. 4. A T cell expressing the TCR can effectively recognize a MART-1 (27-35) epitope polypeptide supported on a T2 cell and secrete IFN-γ, thereby demonstrating the functionality of the receptor. Use of the TCR with a relevant drug target allows for effective drug development.