CARs Targeting TNC and Col11A1 Splice Variants
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Solution Overview
Problem
Current chimeric antigen receptor (CAR)-based therapies are underdeveloped for targeting splice variants of extracellular matrix proteins, such as procollagen 11A1 and tenascin C, which are overexpressed in various cancers, limiting their effectiveness in treating solid and brain tumors.
Innovation Solution
Development of polynucleotides encoding CARs comprising an extracellular target-binding domain that binds to procollagen 11A1 or tenascin C splice variants, a transmembrane domain, and a cytoplasmic signaling domain, including specific antibody fragments and linker sequences, to enable targeted recognition and killing of tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-based therapies target conventional antigens, then therapeutic efficacy is achieved, but 'on target/off cancer' toxicity occurs
Solution Approach 1:
The patent applies local quality by targeting specific splice variants of extracellular matrix proteins (Col11A1 and TNC) that are locally overexpressed in tumor tissues and tumor stroma, rather than targeting conventional antigens that are universally expressed. This localized targeting approach enables the CARs to distinguish between tumor-specific splice variants and normal tissue proteins, thereby reducing off-target toxicity while maintaining therapeutic efficacy in solid and brain tumors.
2Measurement precision
If CARs target splice variants of extracellular matrix proteins, then specificity is improved, but therapeutic development is underdeveloped
Solution Approach 1:
The patent applies preliminary action by providing pre-designed and pre-characterized CAR constructs targeting Col11A1 and TNC splice variants, along with detailed guidance on cell isolation, modification, and expansion protocols. This preliminary preparation of therapeutic components and methodologies accelerates the development process and simplifies manufacturing compared to developing CAR therapies from scratch, thereby improving ease of manufacture while maintaining high target specificity.
3Adaptability or versatility
If CARs target splice variants, then tumor specificity is enhanced, but device complexity increases
Solution Approach 1:
The patent applies universality by designing CARs that can target multiple splice variants of the same protein family (Col11A1 and TNC) using a unified structural platform. The CARs utilize standardized components including IgG1 or IgG4 antibody fragments, CD28 or 4-1BB costimulatory domains, and CD3ζ signaling domains that can be systematically varied to target different splice variants. This modular, universal design enhances tumor specificity across multiple cancer types while avoiding the complexity of creating entirely new CAR structures for each target.
Data Source
AI summary
The application provides chimeric antigen receptors (CARs) that target splice variants of the extracellular matrix proteins tenascin C (TNC) and procollagen 11A1 (Col11A1), and their uses in tumor immunotherapy. The application also provides polynucleotides and vectors that encode the chimeric antigen receptors, as well as host cells comprising the chimeric antigen receptors. The application also provides methods for preparing host cells comprising the chimeric antigen receptors and methods for treating patients using the modified host cells.