CAR Switch Domain for Controllable Immune Cell Activity
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Solution Overview
Problem
Current CAR T-cell therapies for cancer treatment face challenges with cytokine-release syndrome and 'on-target off-tumor' effects, lacking effective non-lethal control mechanisms to manage engineered CAR T-cells.
Innovation Solution
Development of a chimeric antigen receptor (CAR) with a molecular switch domain composed of multimerizing ligand-binding domains that can be controlled by small molecules, allowing for modulation of antigen binding function and immune cell activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T-cell therapy is administered to treat cancer, then therapeutic efficacy is improved, but cytokine-release syndrome and on-target off-tumor effects occur
Solution Approach 1:
The patent introduces a dynamic control system where CAR activity can be switched between active and inactive states using small molecule modulators. The switch domain contains ligand-binding domains that respond to small molecules to dynamically regulate CAR conformation and antigen binding, allowing treatment to be activated when needed and deactivated to prevent adverse effects.
Solution Approach 2:
The patent uses small molecule modulators as intermediaries to control CAR T-cell activity. These small molecules bind to the switch domain's ligand-binding domains and act as mediators that transmit control signals to regulate CAR function, enabling external pharmacological control of the immunotherapy.
2Productivity
If CAR activity is enhanced to improve anti-tumor response, then productivity is improved, but harmful effects increase
Solution Approach 1:
The switch domain enables dynamic adjustment of CAR activity levels. By controlling the conformational state of the switch domain through small molecule binding, the system can be tuned to produce appropriate levels of anti-tumor response while avoiding excessive activation that would lead to harmful adverse effects.
3Ease of manufacture
If conventional CAR design is used, then ease of manufacture is maintained, but control capability is insufficient
Solution Approach 1:
The patent segments the CAR structure into distinct functional modules: an antigen-binding domain, a switch domain containing ligand-binding domains, a transmembrane domain, and a signaling domain. This modular design maintains ease of manufacture through standardized components while enabling advanced control capabilities through the switch domain's response to small molecules.
Solution Approach 2:
The switch domain serves multiple functions: it maintains CAR structural integrity, enables small molecule binding, and controls antigen binding activity. This multi-functionality is achieved by incorporating ligand-binding domains that can respond to various small molecule modulators, providing versatile control capability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach provides more controlled and safer engineered CAR T-cells by enabling precise modulation of CAR activity, reducing adverse effects and enhancing therapeutic efficacy.
Implementation Method 1
a switch domain comprising at least a first multimerizing ligand-binding domain and a second multimerizing ligand-binding domain which are capable of binding to a predetermined multivalent ligand to form a multimer
Data Source
Figure 1A~1B
Figure 2
Figure 3A
AI summary
The present invention relates to the field of cell immunotherapy and more particularly to a new generation of chimeric antigen receptors (CAR), allowing the control of immune cells endowed with such CARs through the interaction with small molecules. More particularly, the present invention relates to chimeric antigen receptor which comprise in at least one ectodomain a molecular switch turning the antigen binding function of the receptor from an off to on state, and vice versa. The present invention thus provides more controlled and potentially safer engineered CAR endowed immune cells, such as T- lymphocytes.