CD99-Targeting CAR Structure for Broad Tumor Heterogeneity
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Solution Overview
Problem
Current CAR-T cell therapy for cancer is limited by the high heterogeneity of tumor cells, leading to off-target effects and a narrow spectrum of treatment due to reliance on single targets, necessitating the development of more effective membrane surface markers for broader tumor targeting.
Innovation Solution
An optimized chimeric antigen receptor (CAR) structure incorporating a signal peptide, single-chain antibody ScFv, CD8 hinge, CD28 transmembrane region, CD28 intracellular domain, 4-1BB co-stimulatory domain, CD3ζ chain, F2A peptide, IL-7, and CCL19, specifically designed to target CD99 antigen on tumor cells, enhancing tumor killing efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a single target is used for CAR-T therapy, then the treatment is simple and easy to implement, but the spectrum of treatment is narrow and cannot address high tumor heterogeneity
Solution Approach 1:
The patent designs a CAR structure with a universal co-stimulatory domain (CD28 or 4-1BB) that can recognize and bind to CD99 antigen across multiple tumor types including Ewing's sarcoma, acute lymphoma/leukemia, and breast cancer. This multi-functional design allows a single CAR-T product to treat heterogeneous tumors expressing CD99, expanding the therapeutic spectrum while maintaining a standardized CAR structure.
Solution Approach 2:
The patent optimizes key parameters of the CAR structure including the signal peptide sequence, ScFv affinity for CD99, co-stimulatory domain composition, and intracellular signaling sequence to enhance tumor killing efficacy. By adjusting these parameters, the CAR achieves broad spectrum activity against CD99-positive tumors while maintaining structural simplicity for clinical implementation.
2Reliability
If conventional CAR-T therapy is used, then the treatment approach is established and reliable, but tumor heterogeneity causes off-target effects and limits treatment effectiveness
Solution Approach 1:
The patent introduces local quality enhancement by adding specific functional domains to the CAR structure: a co-stimulatory domain (CD28 or 4-1BB) for enhanced activation, an intracellular signaling domain for sustained signaling, and optimized extracellular recognition domains for selective binding. These localized functional improvements increase treatment effectiveness while maintaining target specificity to reduce off-target effects.
Solution Approach 2:
The CAR structure incorporates co-stimulatory domains that provide positive feedback signaling when the CAR-T cell recognizes and binds to CD99 antigen on tumor cells. This feedback mechanism enhances the activation and proliferation of CAR-T cells specifically at the tumor site, improving treatment effectiveness while sparing normal tissues from off-target effects.
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 CAR structure significantly enhances tumor killing capabilities, demonstrating improved affinity and efficacy against a broad spectrum of tumors expressing CD99, including Ewing's sarcoma, acute lymphoma/leukemia, and breast cancer, with enhanced cytokine release and proliferation capacity.
Implementation Method 1
the single-chain antibody ScFv is capable of identifying CD99 antigen on the surface of tumor cells
Implementation Method 2
the CAR structures provided exhibit significantly enhanced tumor killing effect compared to one or more reference CARs
Data Source
AI summary
Disclosed herein is an optimized CD99-targeting chimeric antigen receptor and application thereof, wherein a signal peptide, a single-chain antibody ScFv, strepII, a CD8 hinge, a CD28 transmembrane region, a CD28 intracellular domain, an intracellular co-stimulatory domain 4-1BB and CD3ζ chain are sequentially spliced in the chimeric antigen receptor is from the N-terminal to the C-terminal. The single-chain antibody ScFv can specifically recognize CD99 protein on the surface of tumor cells. The CD99-targeting chimeric antigen receptor is used to modify immune cells for the treatment of surface CD99-positive tumors.