KRAS-Mutant TCR Binding Domains for HLA-Specific Tumor Targeting
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Solution Overview
Problem
Current treatments for tumors with KRAS mutations, particularly pancreatic cancer, are limited by acquired resistance and low efficacy of chemotherapy and immunotherapy, with immunotherapy being hindered by a low mutational burden leading to a deficiency of neoantigen-reactive tumor-infiltrating lymphocytes.
Innovation Solution
Development of TCR molecules targeting KRAS mutations, specifically TCR α and β chain variable regions with defined CDR sequences, to enhance antigen specificity and binding to HLA complexes, thereby enhancing immune response against KRAS-mutated cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemotherapy is used to treat KRAS-mutated tumors, then tumor reduction is achieved, but acquired resistance develops and treatment efficacy is limited
Solution Approach 1:
The patent introduces TCR molecules as an intermediary immune mechanism to recognize and eliminate KRAS-mutated tumor cells. The TCR molecules specifically bind to mutant KRAS peptides presented by HLA molecules on tumor cell surfaces, activating T cells to kill target cells through cytotoxic mechanisms, thereby overcoming chemotherapy resistance
Solution Approach 2:
The patent modifies the immune system's ability to recognize tumor cells by engineering TCR molecules with enhanced affinity and specificity for mutant KRAS peptides. The CDR3 regions are specifically optimized to recognize conformational epitopes of mutant KRAS peptides, changing the recognition parameters from conventional chemotherapy targets to immunogenic peptide-HLA complexes
2Reliability
If immunotherapy is used to treat KRAS-mutated tumors, then immune response is activated, but low mutational burden results in deficiency of neoantigen-reactive tumor-infiltrating lymphocytes
Solution Approach 1:
The patent performs preliminary action by ex vivo expansion and activation of T cells with engineered TCR molecules before reinfusion. T cells are pre-loaded with TCRs that specifically recognize KRAS mutant peptides, and are activated ex vivo to generate sufficient numbers of neoantigen-reactive T cells prior to adoptive transfer into the patient
Solution Approach 2:
The engineered TCR molecules serve as intermediaries that bridge the gap between the patient's endogenous T cells and the neoantigens presented by KRAS-mutated tumors. The TCRs enable T cells to recognize and respond to tumor antigens that would otherwise be invisible to the immune system due to low mutational burden
3Measurement precision
If TCR molecules with high antigen specificity are designed, then binding to HLA complexes is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent applies local quality by focusing mutations and optimizations specifically in the CDR3 regions of the TCR, which are the critical antigen-binding sites. The framework regions remain relatively conserved, while the CDR3 loops are engineered to achieve high specificity for mutant KRAS peptides, concentrating the complexity where it is most needed for antigen recognition
Data Source
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AI summary
Provided is a binding protein, comprising a binding domain having antigen specificity for an antigen peptide:HLA complex. The binding domain comprises a T cell receptor (TCR) α-chain variable region and a TCR β-chain variable region. Also provided is a use of the binding protein and a pharmaceutical composition comprising the binding protein in the treatment of cancers associated with the antigen peptide.