Regulatable Chimeric Antigen Receptor Dimerization Switch
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Solution Overview
Problem
Current adoptive cell transfer therapies using Chimeric Antigen Receptors (CARs) lack optimal control over immune responses, leading to safety and efficacy concerns in targeting and inactivating cancer cells.
Innovation Solution
A regulatable chimeric antigen receptor (RCAR) design featuring a dimerization switch that couples an intracellular signaling domain with an extracellular recognition element, allowing for temporal control of immune responses through the use of a dimerization molecule, specifically utilizing a FKBP-FRB based switch mechanism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR therapy is used to target and inactivate cancer cells, then cancer treatment efficacy is improved, but safety control and immune response regulation are worsened
Solution Approach 1:
The CAR is designed with a dimerization switch that allows dynamic regulation between active and inactive states. The switch domain can be activated by administering a dimerization molecule, enabling temporal control over the immune effector response. This dynamic control mechanism resolves the contradiction by allowing the CAR to remain inactive (safe) until deliberately activated (effective).
Solution Approach 2:
A dimerization molecule serves as an intermediary substance that mediates the activation of the CAR. This intermediary allows external control over the immune response, enabling safe storage and transport of the CAR while allowing controlled activation when needed for cancer treatment.
2Ease of manufacture
If CAR is designed with separate binding and signaling domains, then manufacturing and control are improved, but device complexity increases
Solution Approach 1:
The CAR is segmented into distinct functional domains: an extracellular recognition element (binding domain), a transmembrane domain, and an intracellular signaling domain. These segments are separated by switch domains that control their association. This segmentation allows independent optimization and control of each component while maintaining overall functionality.
Solution Approach 2:
The switch domains are nested within the CAR structure, with the first switch domain associated with the binding domain and the second switch domain associated with the signaling domain. This nested arrangement allows compact integration of control mechanisms within the CAR architecture itself.
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
Enables precise activation of immune effector cells, enhancing safety and efficacy by allowing external control over the immune response, thereby improving targeted therapy for cancer treatment.
Implementation Method 1
activation of signaling through the CAR only occurs when the switch domains, and hence the binding domain and the signaling domain, are brought together by a dimerization molecule
Implementation Method 2
the first and second switch domains comprise a FKBP-FRB based switch comprising: (a) a switch domain that comprises a FRB binding fragment or sequence having at least 80, 85, 90, 95, 98 or 99% identity with the FKBP sequence
Data Source
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AI summary
Compositions and methods relating to regulatable chimeric antigen receptors (RCARs), where the intracellular signaling or proliferation of the RCAR can be controlled to optimize the use of an RCAR-expressing cell to provide an immune response, are provided. For example, a RCAR can comprise a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain, or costimulatory ECD domain. An RCAR can be engineered to include an appropriate antigen binding domain that is specific to a desired antigen target and used in the treatment of a disease.