Regulatable CAR With Dimerization Switch For Immune Control
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Solution Overview
Problem
Current adoptive cell transfer therapies with Chimeric Antigen Receptors (CARs) lack optimal control over immune responses, leading to potential safety and efficacy issues in targeting and inactivating cancer cells.
Innovation Solution
Development of regulatable chimeric antigen receptors (RNKR-CARs and RCAR/NKR-CARs) with a dimerization switch mechanism that separates binding and signaling domains, allowing external control over immune effector responses through the use of dimerization molecules, enabling temporal regulation of immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If CAR molecules are used to target and inactivate cancer cells, then cancer cell targeting efficacy is improved, but safety control and specificity are worsened due to lack of temporal regulation
Solution Approach 1:
The CAR molecule is designed with a dimerization switch that allows dynamic control between active and inactive states. The switch domain can be regulated by external stimuli such as small molecules or antibodies, enabling temporal control over the immune effector response. This dynamic regulation mechanism allows the CAR to be activated only when needed, improving safety control while maintaining cancer cell targeting efficacy.
Solution Approach 2:
The CAR molecule is divided into separate functional domains: an antigen binding domain, a transmembrane domain, a switch domain, and a signaling domain. The switch domain is further segmented into two separate domains that must dimerize to activate signaling. This segmentation allows independent control of different functional aspects, enabling temporal regulation of CAR activation while preserving targeting capability.
2Productivity
If CAR activation is continuously active, then cancer cell inactivation is improved, but off-target effects and toxicity are worsened
Solution Approach 1:
The CAR activation is designed to be periodic rather than continuous. The dimerization switch can be activated and deactivated in response to external stimuli, creating pulsed activation cycles. This periodic action allows the CAR to eliminate cancer cells during active phases while remaining inactive during other phases, thereby reducing off-target effects and toxicity associated with continuous activation.
Solution Approach 2:
A dimerization molecule or antibody serves as an intermediary to control CAR activation. This intermediary binds to the switch domain and facilitates dimerization only when present, acting as a temporal gatekeeper. The intermediary mechanism ensures that CAR activation occurs only under specific conditions, preventing unwanted off-target effects while maintaining the ability to inactivate cancer cells when needed.
3Ease of manufacture
If the CAR structure is simplified for ease of manufacture, then manufacturing complexity is reduced, but control over immune response timing is worsened
Solution Approach 1:
The dimerization switch incorporates an intermediary binding interface that can be targeted by small molecules or antibodies. This intermediary mechanism adds temporal control capability without significantly complicating the overall CAR structure. The switch domain can be designed using standard protein engineering techniques, maintaining ease of manufacture while enabling precise control over immune response timing through external modulation of the dimerization interface.
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 enhances the safety and efficacy of immune responses by providing temporal control over CAR activation, reducing off-target effects and improving the specificity and effectiveness of cancer cell targeting.
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
Data Source
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AI summary
Provided are compositions and methods relating to regulatable chimeric antigen receptors (RCARs), natural killer cell receptor CARs (NKR-CARs), and regulatable NKR-CARs (RNKR-CARs), where the intracellular signaling or proliferation of the RCAR or RNKR-CAR can be controlled to optimize the use of an RCAR/NKR-CAR- or RNKR-CAR-expressing cell to provide an immune response. Cells can be engineered to express a RNKR-CAR or to express a RCAR and a NKR-CAR (e.g., inhibitory NKR-CAR). For example, a RCAR or RNKR-CAR 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 or RNKR-CAR 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.