Mesothelin CARs for Solid Tumor Eradication
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Solution Overview
Problem
Current therapies targeting mesothelin for cancer treatment, particularly for solid tumors, have shown limited success, necessitating the development of novel strategies for designing chimeric antigen receptors (CARs) that can induce potent tumor eradication with minimal toxicity and immunogenicity.
Innovation Solution
Development of antibodies and antigen-binding fragments specifically binding to mesothelin, integrated into chimeric antigen receptors (CARs) expressed in genetically engineered immune effector cells, such as T cells, to target and treat mesothelin-expressing cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies targeting mesothelin are used for cancer treatment, then some therapeutic effect is achieved, but the success rate is limited and tumor eradication is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure to create chimeric antigen receptors (CARs) with enhanced binding affinity and specificity for mesothelin. The CAR construct combines the mesothelin-targeting antibody variable region with signaling domains from T cell receptors, fundamentally changing the therapeutic mechanism from simple antibody binding to activated T cell-mediated tumor cell destruction, thereby improving eradication efficacy
Solution Approach 2:
The invention creates a composite therapeutic system by combining the mesothelin-specific antibody (M12) with T cell signaling components (CD3ζ, CD28, 4-1BB domains) to form chimeric antigen receptors. This composite structure integrates target recognition, signal transduction, and T cell activation functions into a single molecular entity, enabling more effective tumor eradication compared to conventional monotherapy
2Reliability
If conventional antibody therapies are used to target mesothelin, then some binding is achieved, but the therapeutic outcome is limited due to minimal tumor eradication
Solution Approach 1:
The patent introduces genetically engineered T cells as intermediary effectors that express mesothelin-specific CARs. These engineered T cells serve as mediators between the antibody-based target recognition and the cytotoxic killing function, enabling selective tumor cell destruction while sparing normal cells that do not express mesothelin, thereby reducing off-target toxicity
Solution Approach 2:
The CAR-expressing T cells possess self-service capabilities through built-in costimulatory domains (CD28, 4-1BB) that provide continuous activation signals. These domains enable the T cells to self-sustain proliferation and cytotoxic activity in the tumor microenvironment without requiring external cytokine support, enhancing tumor eradication while maintaining selectivity and reducing systemic toxicity
Data Source
AI summary
Disclosed herein are anti-mesothelin antibodies and antigen-binding fragments, chimeric antigen receptors (“CARs”) having these anti-mesothelin antibodies and antigen-binding fragments (“mesothelin CARs”) and genetically modified immune effector cells having such mesothelin CARs. Polynucleotides encoding the anti-mesothelin antibodies and antigen-binding fragments and mesothelin CARs are also provided herein. Compositions comprising anti-mesothelin antibodies and antigen-binding fragments and mesothelin CARs are also provided herein. The present disclosure also relates to uses of the anti-mesothelin antibodies and antigen-binding fragments and genetically modified immune effector cells having such mesothelin CARs in cancer treatment.