Anti-CD19 CAR-T Cell CD8α Hinge Design for Cytokine Control
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Solution Overview
Problem
Anti-CD19 CAR-T cell therapy causes severe side effects such as cytokine release syndrome and neurotoxicity due to rapid cell proliferation and excessive cytokine release, limiting its widespread application in treating leukemia and lymphoma.
Innovation Solution
A modified CD19-BBz CAR fusion protein with altered hinge, trans-membrane, and intracellular regions, enhancing spatial configuration and reducing cell proliferation, and a non-functional EGFR as a suicide marker for targeted tumor killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD19 CAR-T cell therapy is used to treat leukemia and lymphoma, then therapeutic efficacy is improved, but severe side effects such as cytokine release syndrome and neurotoxicity occur due to rapid cell proliferation and excessive cytokine release
Solution Approach 1:
The patent modifies the hinge region amino acid sequence of the CAR molecule (changing from native CD8α sequence to a modified sequence with specific substitutions), which alters the spatial configuration and signaling properties of the CAR-T cells. This parameter change in the molecular structure reduces excessive cytokine production while preserving anti-tumor efficacy
Solution Approach 2:
The invention introduces a suicide gene (inducible caspase 9) into the CAR-T cells, creating a localized safety mechanism within the therapeutic cells. This local quality enhancement allows controlled elimination of overproliferating CAR-T cells without affecting normal cells, thereby reducing harmful side effects
2Object-affected harmful factors
If the hinge region and trans-membrane segment of CAR are modified to reduce cell proliferation, then safety is improved, but tumor killing ability may be compromised
Solution Approach 1:
The patent carefully designs the hinge region modification to achieve optimal spatial configuration that balances two functions: reducing excessive activation signals that cause overproliferation, while maintaining sufficient signaling capacity for effective tumor cell killing. The specific amino acid substitutions create this balanced parameter state
Solution Approach 2:
The suicide gene system provides negative feedback control: when CAR-T cells proliferate excessively and cause harmful effects, the inducible caspase 9 can be activated to eliminate these cells, creating a feedback loop that maintains safety without compromising the overall therapeutic function
Data Source
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AI summary
The present disclosure provides a chimeric antigen receptor. The chimeric antigen receptor comprises an extracellular segment, comprising a single-chain antibody region specifically binding to an antigen human CD19 and a hinge region, wherein the single-chain antibody region comprises a heavy chain variable region and a light chain variable region of the single-chain antibody, and the hinge region comprises an extracellular domain of human CD8 alpha (CD8a) of 55 amino acid residues and three alanine residues (AAA) located at the N-terminal of the extracellular domain of human CD8a; a trans-membrane segment, comprising a trans-membrane domain of human CD8α linked to the hinge region of the extracellular segment and embedded in cell membrane of T lymphocyte, and an intracellular segment, comprising an intracellular domain of human CD8α, an intracellular domain of molecule 4-1BB and an intracellular domain of CD3 ζ chain, wherein the intracellular domain of human CD8α comprises seven amino acid residues and linked to the trans-membrane domain of human CD8α.