GD2 CAR-T Cells With Self-Destructive Domain
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Solution Overview
Problem
Current CAR-T cell therapies for tumors, particularly neuroblastoma, face challenges in targeting tumor tissues effectively and persisting in the body, leading to limited therapeutic efficacy and potential antibody resistance.
Innovation Solution
A GD2-based lentiviral chimeric antigen receptor is developed, comprising an antigen-binding domain, transmembrane domain, costimulatory signaling domain, CD3ζ signaling domain, and a self-destructive domain, with specific amino acid sequences for enhanced binding to GD2 antigens, improved immune stimulation, and safety features like apoptosis induction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-GD2 antibody therapy is used, then initial clinical success is achieved, but the antibody cannot penetrate tumor tissues effectively and cannot persist in the body for a long time
Solution Approach 1:
The patent replaces the mechanical/chemical system of administered antibodies with a biological system of genetically modified T cells that express CARs. These CAR-T cells can actively seek and bind to GD2-expressing tumor cells, providing both effective targeting and long-term persistence through their ability to proliferate and survive in the tumor microenvironment.
Solution Approach 2:
The patent changes the fundamental parameter of the therapeutic agent from a passive antibody molecule to an active living T cell system. This parameter change enables the therapeutic agent to not only bind to the target but also to persist, proliferate, and exert prolonged anti-tumor effects within the body.
2Reliability
If anti-GD2 antibody therapy is used, then tumor targeting is achieved, but the antibody structure induces resistance and increases difficulty in retreatment
Solution Approach 1:
The patent replaces the chimeric antibody structure with a human T cell-based system expressing chimeric antigen receptors. This substitution eliminates the immunogenicity issues associated with mouse-derived components while maintaining GD2 targeting capability, thereby preventing antibody-induced resistance and enabling potential retreatment options.
3Reliability
If conventional CAR-T cell therapy is used, then tumor recognition is improved, but the binding effect and immune effector domains need further improvement
Solution Approach 1:
The patent optimizes the CAR structure by selecting specific scFv sequences with demonstrated high affinity for GD2 and by configuring appropriate costimulatory domains (CD28 and/or 4-1BB) alongside the CD3ζ signaling domain. These parameter optimizations enhance both the binding strength to GD2 and the immune effector function of the CAR-T cells.
Data Source
AI summary
The present application relates to a GD2-based chimeric antigen receptor comprising an antigen-binding domain, a transmembrane domain, a costimulatory signaling domain, a CD3ζ signaling domain, and a self-destructive domain in tandem arrangement; wherein the antigen-binding domain binds to a tumor surface antigen, wherein the tumor surface antigen is GD2, and the antigen-binding domain is a single-chain antibody against the tumor surface antigen GD2, wherein the self-destructive domain is a caspase 9 domain.