NKG2D Transmembrane CAR-NK Design for NK-Specific Tumor Killing
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for natural killer (NK) cells, derived from conventional CAR-T cell therapies, do not optimally function due to differences in activation signaling pathways between NK and T cells, and existing CAR-NK structures lack optimal design for transmembrane regions, particularly for NKG2D, limiting their anti-tumor efficacy.
Innovation Solution
Designing optimized CAR structures for NK cells with varied transmembrane regions and intracellular co-stimulatory domains tailored to NK cell activation pathways, incorporating NKG2D TM regions, and enhancing the CAR-NK cells with specific antigen-binding regions targeting BCMA and ROR1 to improve tumor targeting and killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional CAR structures from CAR-T cell therapies are used in NK cells, then the CAR structure is standardized and easy to manufacture, but the anti-tumor functionality is not fully exerted due to differences in activation signaling pathways between NK and T cells
Solution Approach 1:
The patent applies local quality by customizing specific components of the CAR structure for NK cells while maintaining the overall modular CAR architecture. The intracellular signaling domain is specifically optimized for NK cell activation pathways (using CD3ζ combined with NK-specific co-stimulatory domains like 2B4, CD27, or CD28), and the transmembrane region is selected from NK cell receptors (NKG2D, CD16, or CD64) rather than T cell receptors. This localized optimization ensures the CAR functions properly in NK cells while retaining manufacturing standardization benefits.
2Reliability
If the NKG2D transmembrane region is used in CAR-NK cells, then the cell activation and killing effects are enhanced, but the structural design complexity increases due to lack of fine design for the NKG2D TM region
Solution Approach 1:
The patent applies parameter changes by systematically evaluating and optimizing the NKG2D transmembrane region sequence to identify the optimal configuration. The patent compares different NKG2D TM region sequences and selects the one that provides the best balance between activation enhancement and structural simplicity. This parameter optimization approach transforms the complex design space into a defined optimal solution that can be consistently manufactured.
3Reliability
If multiple CAR structures with different transmembrane regions and co-stimulatory domains are designed and screened, then the optimal CAR structure for NK cells is obtained, but the development time and complexity increase
Solution Approach 1:
The patent applies preliminary action by pre-selecting and validating a limited set of promising CAR structures before full-scale screening. The patent identifies key combinations of transmembrane regions (NKG2D, CD16, CD64) and co-stimulatory domains (2B4, CD27, CD28) based on NK cell biology, then focuses screening efforts on these pre-selected candidates. This preliminary filtering approach reduces the overall screening time while still identifying the optimal CAR structure for NK cells.
Data Source
AI summary
The present invention relates to an enhanced chimeric antigen receptor and use thereof, including a nucleic acid molecule for encoding a chimeric antigen receptor containing an NKG2D transmembrane region, a corresponding chimeric antigen receptor, a carrier, an immune effector cell, a preparation method and a product thereof, a pharmaceutical composition, pharmaceutical use, and a tumor or cancer treatment method. The present invention has the advantages of high CAR expression efficiency, rapid NK cell proliferation, strong killing ability against tumor cells, high specificity, long duration of killing effect, and the like.