Switchable CAR Receptor Tag Segmentation
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Solution Overview
Problem
Conventional CAR technology faces challenges such as uncontrolled immune responses, adverse events, and the limitation of targeting a single antigen, leading to the development of tumor escape variants.
Innovation Solution
A switchable chimeric antigen receptor (CAR) is developed, comprising a tag or tag-binding domain, an extracellular hinge and transmembrane domain, and an intracellular signaling domain. This CAR can bind to a targeting module, allowing for antigen-specific targeting and reversible activation, thereby overcoming the limitations of conventional CARs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CARs are used to target tumor antigens, then anti-tumor response is activated, but uncontrolled immune responses and adverse events occur
Solution Approach 1:
The CAR system is segmented into two independent components: a universal CAR expressed on immune cells that recognizes a tag, and a separate targeting module that binds to both the tag and the tumor antigen. This segmentation allows independent control of the immune cell activation and tumor targeting functions, enabling safer regulation of immune responses while maintaining anti-tumor efficacy.
Solution Approach 2:
A universal tag (e.g., FLAG® tag) serves as an intermediary element between the CAR on immune cells and the targeting module. The CAR binds to the tag, and the targeting module bridges the tag and the tumor antigen, creating a controllable intermediate step that enables regulated immune activation and reduces uncontrolled adverse events.
2Reliability
If conventional CARs target a single antigen, then specific anti-tumor response is achieved, but tumor escape variants develop
Solution Approach 1:
The universal CAR is designed to recognize a universal tag rather than a specific tumor antigen. By pairing this universal CAR with different targeting modules that can bind to various tumor antigens, the system achieves multi-functionality and adaptability, allowing it to target different antigens and prevent tumor escape variants while maintaining reliable anti-tumor responses.
3Productivity
If CAR activation is continuous, then vigorous T cell expansion occurs, but tumor lysis syndrome and cytokine release syndrome develop
Solution Approach 1:
The system enables dynamic control of CAR activation through the separate administration of the targeting module. The universal CAR is pre-expressed on immune cells, but activation only occurs when the targeting module is administered. This dynamic control allows T cell expansion to be adjusted according to treatment needs, achieving productivity while avoiding harmful over-activation and cytokine release syndrome.
4Power
If conventional CARs are engineered with multiple signaling domains, then T cell activation is enhanced, but off-target effects increase
Solution Approach 1:
The tumor antigen recognition function is extracted from the CAR and placed in the separate targeting module. The universal CAR only recognizes the universal tag, which has no biological function in the body. This extraction eliminates off-target effects caused by the CAR binding to endogenous antigens, while the targeting module provides the necessary antigen-specific activation power when administered.
Data Source
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AI summary
The present invention relates to a switchable chimeric antigen receptor (CAR) comprising a tag or tag-binding domain, which is capable of binding a tag-binding domain or a tag of a targeting module, wherein the targeting module comprises a target cell-binding domain. The invention also relates to a nucleic acid, vector or cell comprising a nucleotide sequence encoding the switchable CAR, a pharmaceutical composition comprising a cell comprising a nucleotide sequence encoding the switchable CAR, a kit and the use as a medicament, in particular for use in the treatment of cancer, infectious disease or autoimmune disease.