Bispecific BCMA-CD19 CAR for Deep B Cell Depletion
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Solution Overview
Problem
Current treatments for autoimmune diseases, such as systemic lupus erythematosus, are inadequate, with existing therapies like rituximab and obexelimab failing to meet primary endpoints in clinical trials, and there is a need for more effective B cell depletion strategies.
Innovation Solution
Development of a bispecific chimeric antigen receptor (CAR) that targets both BCMA and CD19, comprising specific variable regions with high sequence identity to SEQ ID NOs, which can be expressed in T cells or NK cells to achieve targeted B cell depletion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies against B cell surface markers (e.g., rituximab anti-CD20, obexelimab anti-CD19) are used for B cell depletion, then B cell depletion is achieved, but clinical trials failed to meet primary endpoints and treatment effectiveness is insufficient
Solution Approach 1:
The patent combines two different antigen-specific binding regions (anti-BCMA and anti-CD19) into a single bispecific CAR structure. This merging allows the CAR to simultaneously target both BCMA and CD19 antigens on B cells, enhancing the depletion effectiveness by engaging multiple targets rather than relying on a single antigen, thereby resolving the contradiction between treatment effectiveness and B cell depletion efficiency
Solution Approach 2:
The bisspecific CAR performs multiple functions by recognizing and binding to two different antigens (BCMA and CD19) that are both expressed on B cells. This multi-functionality ensures comprehensive B cell targeting, including conventional B cells, plasma cells, and B cell subsets that may express one or both antigens, thereby improving both the reliability of treatment effectiveness and the productivity of B cell depletion
2Duration of action of stationary object
If existing B cell depletion therapies are used, then some B cell reduction is achieved, but long-term remission is not sustained and drug-free remission is not achieved
Solution Approach 1:
The bisspecific CAR introduces dynamic adaptability by switching between or combining binding to BCMA and CD19 antigens based on the cellular context. This dynamic targeting allows the CAR to maintain effective engagement with B cells throughout different stages of depletion and during follow-up periods, extending the duration of action and supporting sustained remission without requiring continuous medication
Solution Approach 2:
By targeting both BCMA and CD19, the bisspecific CAR ensures continuous and comprehensive B cell depletion action without gaps. The dual antigen targeting covers the entire B cell differentiation pathway from naive B cells to plasma cells, maintaining uninterrupted depletion pressure and enabling long-term remission sustainability
3Productivity
If broader B cell targeting is achieved, then deeper depletion is possible, but off-target effects and safety issues may increase
Solution Approach 1:
The bisspecific CAR applies local quality by selectively targeting BCMA and CD19 antigens that are specifically expressed on B cells and their subsets. The antigen-specific binding regions ensure that the CAR only engages with cells expressing these markers, maintaining high specificity. This localized targeting approach achieves deep depletion of relevant B cell populations while avoiding off-target effects on other cell types
Data Source
AI summary
The present disclosure provides bispecific chimeric antigen receptors targeting BCMA and CD19. The CAR may comprise an scFv targeting BCMA and an scFv targeting CD19, a hinge region, a transmembrane domain, a co-stimulatory region, and a cytoplasmic signaling domain. The chimeric antigen receptors can be used to treat autoimmune disorders or cancer.