Low-Affinity c-MET CAR Constructs for Selective Tumor Killing
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Solution Overview
Problem
Existing CAR-T cell therapies targeting c-MET face challenges such as collateral damage to healthy tissues due to high affinity binding, leading to on-target, off-tumor toxicity and T cell exhaustion, particularly in treating solid tumors.
Innovation Solution
Development of affinity-tuned chimeric antigen receptors (CARs) with modified VH and VL CDR3 domains in anti-c-MET scFvs to reduce binding affinity, combined with costimulatory and activation domains, to selectively target and kill c-MET-expressing cancer cells while minimizing healthy tissue damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high affinity anti-c-MET CARs are used to effectively target cancer cells, then tumor cell killing efficacy is improved, but on-target off-tumor toxicity increases due to binding to healthy tissues with low c-MET expression
Solution Approach 1:
The patent applies parameter changes by modifying the binding affinity of the CAR's antigen binding domain through amino acid substitutions in the CDR3 loop. This creates a spectrum of CAR variants with different affinities, allowing selection of optimal affinity that achieves tumor cell killing while minimizing toxicity to healthy tissues with low c-MET expression
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the CDR3 loop region of the antibody variable domain. These focused amino acid substitutions at specific positions (e.g., residues 98-104 in SEQ ID NO: 2) alter the local binding interface properties to reduce affinity selectively, thereby differentiating between high-expression tumor cells and low-expression healthy cells
2Reliability
If high affinity anti-c-MET CARs are used to effectively target cancer cells, then tumor cell killing efficacy is improved, but T cell exhaustion increases leading to poor persistence and relapse
Solution Approach 1:
The patent applies parameter changes by systematically varying the binding affinity parameter of the CAR through amino acid substitutions. This creates an optimal affinity range that provides sufficient tumor cell recognition and killing while avoiding excessive tonic signaling that causes T cell exhaustion, thereby improving long-term T cell persistence and preventing relapse
3Object-affected harmful factors
If affinity is reduced to minimize healthy tissue damage, then on-target off-tumor toxicity is reduced, but tumor cell killing efficacy may be compromised
Solution Approach 1:
The patent applies parameter changes by creating a series of CAR variants with progressively reduced affinity through specific amino acid substitutions. This allows identification of an optimal affinity threshold that is low enough to prevent healthy tissue toxicity but high enough to maintain effective tumor cell killing, achieving a balance between safety and efficacy
Data Source
AI summary
The present disclosure relates to low affinity chimeric antigen receptors (CARs) and CAR-T cells, which provide cytotoxicity against tumors overexpressing the proto-oncogene c-MET and alleviate on-target, off-tumor toxicities. The CAR-T cells of the present disclosure comprise low affinity anti-c-MET scFvs, which facilitate enhanced anti-tumor activity and a reduced rate of tumor relapse.