Combined CD19/CD20 Chimeric Receptor Against Antigen Escape
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Solution Overview
Problem
Existing CD19 chimeric antigen receptor (CAR)-T cell therapy for treating B-cell malignancies faces challenges with antigen escape, leading to poor treatment outcomes and high relapse rates due to tumor cells down-regulating or deleting the CD19 antigen expression.
Innovation Solution
Development of a combined chimeric antigen receptor (CAR) targeting both CD19 and CD20, comprising a specific structure with linked scFv domains for both antigens, enhancing tumor recognition and reducing immune escape by targeting two antigens simultaneously.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If CD19 CAR-T cell therapy is used to treat B-cell malignancies, then initial response rate is high (complete remission achieved in 90% of patients), but relapse rate increases (11% of patients relapsed) due to antigen escape
Solution Approach 1:
The CAR-T cell therapy is segmented into dual-targeting capability by incorporating two separate scFv domains (anti-CD19 and anti-CD20) within a single CAR structure. This allows the system to independently recognize and respond to both antigens, preventing reliance on a single antigen target and thereby reducing relapse rates due to antigen escape.
Solution Approach 2:
The CAR-T cell construct is designed with multi-functionality by integrating both CD19 and CD20 targeting capabilities into a single receptor structure. This universal design enables the CAR-T cells to effectively target and kill tumor cells expressing either CD19, CD20, or both antigens, thereby improving long-term treatment reliability.
2Device complexity
If single-target CD19 CAR is used, then treatment simplicity is maintained, but tumor cells can escape by down-regulating or deleting CD19 expression
Solution Approach 1:
The patent merges two separate single-target CAR designs (CD19 CAR and CD20 CAR) into a single dual-targeting CAR construct. This combining approach maintains the simplicity of single-CAR administration while providing dual antigen recognition capability, effectively preventing tumor cells from escaping by down-regulating or deleting a single antigen.
Solution Approach 2:
The CAR structure transitions from one-dimensional single-antigen targeting to two-dimensional dual-antigen targeting by incorporating two scFv domains. This dimensional expansion in antigen recognition space ensures that tumor cells must lose both CD19 and CD20 expression to escape, significantly increasing the barrier to antigen escape.
3Reliability
If dual-targeting CAR-T cells are developed, then antigen escape is prevented by targeting both CD19 and CD20, but CAR structure complexity increases
Solution Approach 1:
The dual-targeting CAR structure is segmented into distinct functional modules: an anti-CD19 scFv domain, an anti-CD20 scFv domain, a hinge region, a transmembrane domain, and intracellular signaling domains. This modular segmentation allows for systematic design and assembly of the complex structure while maintaining ease of construction through standardized components.
Solution Approach 2:
The CAR construct employs a nested arrangement where the anti-CD19 and anti-CD20 scFv domains are nested within the same extracellular region, with the hinge region nesting between them. This nested structure efficiently packs multiple functional elements into a compact configuration, reducing overall structural complexity despite dual-targeting capability.
Data Source
AI summary
The present invention provides a combined chimeric antigen receptor targeting CD19 and CD20 and application thereof. Specifically, the present invention provides a combined chimeric antigen receptor targeting CD19 and CD20, which comprises a scFv targeting CD19 and CD20, a hinge region, a transmembrane region, and an intracellular signaling domain. The present invention provides a nucleic acid molecule encoding the chimeric antigen receptor and a corresponding expression vector, a CAR-T cell, and applications thereof. The experimental results show that the chimeric antigen receptor provided by the present invention shows extremely high killing ability against tumor cells. The chimeric antigen receptor of the present invention targets CD19 and/or CD20 positive cells and can be used to treat CD19 and/or CD20 positive B-cell lymphoma, leukemia and other diseases.