High-Affinity Mesothelin CAR for Solid Tumor Targeting
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Solution Overview
Problem
Current immunotherapies for solid tumors, such as immune checkpoint inhibitors and CAR-T cell therapies, are hindered by fibrous tissues surrounding tumors, making drug delivery difficult and reducing therapy efficiency. There is a need for a cancer treatment method that targets a protein specifically overexpressed on the surface of solid cancer cells with high affinity.
Innovation Solution
Development of an anti-mesothelin antibody or antigen-binding fragment with increased affinity for mesothelin, along with a chimeric antigen receptor (CAR) comprising an antigen-binding domain, hinge domain, transmembrane domain, and intracellular signaling domain, to enhance targeting and delivery to mesothelin-positive cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapies (immune checkpoint inhibitors and CAR-T cell therapies) are used for solid tumors, then general immunotherapy mechanisms are activated, but fibrous tissues surrounding tumors interfere with drug delivery and reduce therapy efficiency
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's binding affinity parameters through amino acid substitutions in the CDR regions. The engineered antibody exhibits significantly increased affinity for mesothelin compared to conventional antibodies, enabling effective targeting of solid tumors despite the presence of fibrous tissues that normally hinder drug delivery.
2Measurement precision
If an antibody with high affinity for mesothelin is developed to target solid cancer cells, then specific binding to cancer cells is improved, but the complexity of antibody engineering increases
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions specifically in the complementarity-determining regions (CDR1, CDR2, CDR3) of the antibody variable domains. This localized modification approach achieves high binding affinity for mesothelin while minimizing overall structural changes and engineering complexity.
Solution Approach 2:
The patent systematically varies amino acid parameters at specific positions in the CDR regions to optimize binding affinity. Through controlled parameter changes in the antibody sequence, the invention achieves precise high-affinity binding to mesothelin while maintaining a relatively straightforward engineering approach.
3Productivity
If CAR-T cell therapy is used to treat solid tumors, then T cell activation is achieved, but fibrous tissues prevent effective cell infiltration and reduce cytotoxic ability
Solution Approach 1:
The patent enhances the productivity (cytotoxic ability) of CAR-T cells by engineering the antigen-binding domain with increased affinity for mesothelin. This parameter change in binding strength enables CAR-T cells to effectively recognize and attack mesothelin-positive solid tumor cells even when facing fibrous tissue barriers that normally impede cell infiltration.
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 anti-mesothelin antibody and CAR improve binding affinity to mesothelin-expressing cancer cells, enhancing therapeutic efficacy against cancers like pancreatic cancer, ovarian cancer, and non-small cell lung cancer by increasing cytotoxic ability against these cells.
Implementation Method 1
an anti-mesothelin chimeric antigen receptor that has increased affinity for mesothelin and binds specifically to mesothelin
Data Source
AI summary
Provided is an anti-mesothelin chimeric antigen receptor that has increased affinity for mesothelin and binds specifically to mesothelin. An anti-mesothelin chimeric antigen receptor according to one aspect has increased affinity for mesothelin and exhibits a specific binding ability to mesothelin, and accordingly, can be useful for the prevention or treatment of cancer in which mesothelin is overexpressed.