Dual-Target CAR-T Structure With CD28 Mutation Against Immune Escape
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Solution Overview
Problem
Current CAR-T cell therapies targeting either BCMA or CD19 have limitations in therapeutic scope, immune escape, and safety concerns due to single-target approaches.
Innovation Solution
Development of a CAR-T cell that simultaneously targets BCMA and CD19 with a modified intracellular CD28 co-stimulatory domain, specifically mutating the YMNM motif to YMFM in the CD28 mutant, allowing parallel expression of BCMA and CD19-mutant CARs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If single-target CAR-T cells (targeting either BCMA or CD19) are used, then the therapy is simpler to develop and implement, but the therapeutic scope is limited and immune escape occurs more frequently
Solution Approach 1:
The patent combines two separate CAR structures (BCMA CAR and CD19 CAR) into a single dual-targeted CAR-T cell. The bispecific CAR contains both BCMA-binding and CD19-binding domains within one receptor molecule, allowing simultaneous targeting of both antigens through a single engineered cell product, thereby expanding therapeutic scope while managing complexity
Solution Approach 2:
The dual-targeted CAR-T cell is designed to perform multiple functions: it can recognize and bind to both BCMA and CD19 antigens, activate T cells through multiple signaling pathways, and eliminate tumor cells expressing either antigen. This multi-functionality allows a single CAR-T product to address diverse tumor types and prevent immune escape mechanisms
2Reliability
If single-target CAR-T cells are used, then the targeting mechanism is simpler, but immune escape by tumors becomes more likely
Solution Approach 1:
The patent merges BCMA and CD19 targeting capabilities into a single bispecific CAR molecule that expresses both antigen-binding specificities. This allows the T cell to simultaneously engage both antigens on tumor cells, creating a more reliable anti-escape mechanism where tumors would need to lose both antigens simultaneously to escape therapy
Solution Approach 2:
The bispecific CAR structure functions as a composite molecular construct combining different antigen-binding domains (anti-BCMA and anti-CD19) within a single receptor framework. This composite structure provides redundant targeting capability, improving reliability by requiring tumors to develop multiple resistance mechanisms simultaneously
3Productivity
If wild-type CD28 co-stimulatory domain is used in CAR-T cells, then the structure is simpler, but therapeutic efficacy and persistence are reduced
Solution Approach 1:
The patent applies parameter changes to the CD28 co-stimulatory domain by mutating specific amino acid residues (N71F and N79F substitutions in the YMNM motif to YMFM). These point mutations alter the biochemical properties of the CD28 domain, enhancing its co-stimulatory signaling capacity and improving T cell activation, proliferation, and persistence without changing the overall CAR structure
Data Source
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AI summary
Provided are CAR-T cells targeting BCMA and CD19. Specifically, provided is a parallel expression structure for chimeric antigen receptors (CARs) for B cell maturation antigen (BCMA) and a CD19 antigen molecules, and optimizes a CD28 costimulatory domain motif. Further provided is a use of the chimeric antigen receptors for adoptive T cell therapy for B cell-related conditions.