Mutant KRAS-Specific TCR for Selective Tumor Cell Killing
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Solution Overview
Problem
Current treatments for KRAS-mutant solid tumors face challenges due to the lack of specificity in targeting KRAS proteins, leading to toxicity issues from indiscriminate inhibition of both wild-type and mutant proteins, and limited efficacy of downstream inhibitors due to feedback mechanisms.
Innovation Solution
Development of a novel antigen-binding protein, specifically a T cell receptor (TCR) that binds with high affinity to KRAS mutant epitopes, particularly G12 mutant epitopes, with high expression and membrane stability, and mediates targeted killing of antigen-positive cells without alloreactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule drugs targeting KRAS are used to directly inhibit KRAS protein activity, then KRAS mutant activity is suppressed, but indiscriminate inhibition of both wild-type and mutant KRAS proteins causes unacceptable toxicity
Solution Approach 1:
The TCR is engineered to recognize specifically the mutant KRAS epitope presented by HLA-A*11, distinguishing it from wild-type KRAS through localized amino acid differences at codon 12 (G12D, G12V, or G12C mutations). This localized recognition ensures selective targeting of mutant cells while sparing wild-type cells, resolving the toxicity issue of non-specific inhibition
Solution Approach 2:
The invention uses HLA-A*11 as an intermediary molecule that presents the mutant KRAS epitope to the TCR. The TCR recognizes the peptide-MHC complex rather than the native KRAS protein directly, enabling specific identification of mutant cells through the immunopresentation pathway while avoiding off-target effects
2Reliability
If downstream inhibitors targeting RAF/MEK/ERK or PI3K/AKT/mTOR pathways are used, then KRAS signaling is blocked, but extensive feedback mechanisms limit clinical trial efficacy
Solution Approach 1:
The TCR selectively extracts and targets only the mutant KRAS signal source by recognizing the mutated epitope presented on tumor cell surfaces. By eliminating the mutant KRAS-expressing cells directly through T cell-mediated cytotoxicity, the upstream mutation-driven signaling is removed without triggering downstream feedback adaptations that limit other approaches
3Reliability
If TCRs specific for KRAS mutant antigens are developed, then specific killing of antigen-positive cells is achieved, but expression stability and membrane stability must be optimized
Solution Approach 1:
The TCR construct parameters were optimized by modifying the constant regions, signal peptide sequences, and chain pairing to enhance expression levels and membrane stability. These parameter changes maintain the variable region specificity for mutant KRAS epitopes while improving the overall stability and functionality of the TCR on T cell surfaces
Data Source
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AI summary
Disclosed are an antigen-binding protein, a multispecific antibody, a nucleic acid encoding an antigen-binding protein or a multispecific antibody, a vector comprising the nucleic acid, a cell comprising an antigen-binding protein, a multispecific antibody, a nucleic acid or a vector, and a method for preparing a cell. Further disclosed are a conjugate or composition comprising an antigen-binding protein or a multispecific antibody, a method for preventing and/or treating a disorder by using an antigen-binding protein, a multispecific antibody or a cell, and a method for detecting the presence of a disorder in a subject.