KRAS G12V-Specific T Cell Receptor for Targeted Tumor Recognition
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Solution Overview
Problem
Current technologies are inadequate in isolating and utilizing T-cell receptors (TCRs) specific for KRAS G12V antigen mutations, which are prevalent in various human malignancies, limiting effective immunotherapy for tumors such as pancreatic, colon, and lung cancers.
Innovation Solution
Development of a T-cell receptor (TCR) capable of specifically binding to KRAS G12V antigen peptides, particularly VVGAVGVGK or VVVGAVGVGK, and its encoding nucleic acid sequences, allowing for transduction into T cells to target and treat KRAS G12V-related diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current immunotherapies are used, then general cancer treatment is possible, but they lack effective T-cell receptors specific to KRAS G12V antigen, limiting their ability to target and treat KRAS G12V-related cancers effectively
Solution Approach 1:
The patent designs TCRs with specific CDR regions (CDR1, CDR2, CDR3) that have localized amino acid sequences optimized for binding to the KRAS G12V peptide-MHC complex. The CDR3 regions in particular are engineered with specific sequences (e.g., α-CDR3: ASLKGNNDMR, β-CDR3: ASSSSRWEQQF) that provide high-affinity and specific recognition of the mutated antigen, enabling reliable and specific immunotherapy for KRAS G12V-related cancers
2Measurement precision
If TCRs are designed with defined CDR regions for specific binding, then recognition of KRAS G12V antigen is achieved, but the complexity of TCR design and characterization increases
Solution Approach 1:
The TCR is divided into functional segments: variable domains (Vα, Vβ) containing CDR1, CDR2, and CDR3 regions for antigen recognition, and constant domains (Cα, Cβ) for signal transduction. This segmentation allows independent optimization of each CDR region's amino acid sequence to achieve precise binding to the KRAS G12V peptide-MHC complex while maintaining manageable design complexity through modular construction
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The TCR effectively recognizes and targets KRAS G12V antigen-presenting cells, providing a therapeutic approach for tumors like pancreatic, colon, and lung cancers by enhancing cellular immunotherapy.
Implementation Method 1
T-cell receptor (TCR) is a membrane protein on the surface of T cells, which can recognise the corresponding antigenic peptides on the surface of target cells
Implementation Method 2
Then, the interaction of other membrane molecules in both of the T cell and APC occurs and the subsequent cell signaling and other physiological responses are initiated so that a range of different antigen-specific T cells exert immune effects on their target cells
Data Source
AI summary
Provided is a T cell receptor (TCR) capable of specifically binding to KRAS G12V mutant antigens; the mutant antigen short peptide VVGAVGVGK is capable of forming a complex with HLA A1101, and the TCR specifically binds to said complex. Also provided in the present invention are a nucleic acid molecule encoding the TCR and a vector comprising the nucleic acid molecule. Also provided are TCR-transduced cells.