CD19 CAR with iCasp9 Suicide Domain for Toxicity Control
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Solution Overview
Problem
Existing CD19-based chimeric antigen receptors for CAR-T cell therapy have strong toxicity and side effects due to immune factor storms, necessitating the development of a receptor with lower side effects and enhanced therapeutic efficacy.
Innovation Solution
A CD19-based chimeric antigen receptor is designed with an antigen-binding domain specific to CD19, a transmembrane domain, a costimulatory signal transduction region comprising a CD27 domain, and an inducible suicide fusion domain iCasp9, which together enhance T cell stimulation and provide a safe removal mechanism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CD19-based chimeric antigen receptor is used for CAR-T cell therapy, then tumor cell killing effect is achieved, but immune factor storm occurs causing strong toxicity and side effects
Solution Approach 1:
The patent segments the costimulatory signal transduction region into two distinct domains: CD27 domain for enhanced T cell stimulation and CD28 domain for controlled activation. This segmentation allows differential function where CD27 provides strong killing effect while CD28 provides regulated costimulation, reducing immune factor storm toxicity while maintaining tumor cell killing efficacy
Solution Approach 2:
The patent creates a composite chimeric antigen receptor structure combining multiple functional domains: antigen-binding domain (anti-CD19 scFv), transmembrane domain (CD8α), dual costimulatory signal transduction regions (CD27 and CD28 domains), and intracellular signaling domain (CD3ζ). This composite structure integrates enhanced killing capability through CD27 with controlled activation through CD28, resolving the contradiction between efficacy and toxicity
2Productivity
If strong T cell stimulation is provided to enhance therapeutic effect, then tumor cell killing effect is improved, but immune factor storm is triggered causing strong side effects
Solution Approach 1:
The patent applies local quality by assigning different functional characteristics to different parts of the costimulatory signal transduction region. The CD27 domain provides strong T cell stimulation locally to enhance therapeutic effect, while the CD28 domain provides moderate costimulation locally to control activation and prevent immune factor storm. This spatial differentiation of functional quality resolves the contradiction between productivity and harmful factors
Data Source
AI summary
The present application provides a chimeric antigen receptor and application thereof. The chimeric antigen receptor comprises an antigen-binding domain, a transmembrane domain, a costimulatory signal transduction region, a CD3ζ signal transduction domain, and an inducible suicide fusion domain in tandem arrangement; wherein the antigen-binding domain binds to a tumor surface antigen and the tumor surface antigen is CD19.