Modular CAR Signaling With Small-Molecule Shutdown Control
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Solution Overview
Problem
Existing chimeric antigen receptor (CAR) T-cell therapies face challenges such as unpredictable toxicities, including macrophage activation syndrome and 'on-target off-tumor' toxicity, which are difficult to predict and manage, and current safety mechanisms like suicide genes are limited in controlling potency and timing.
Innovation Solution
A CAR signaling system where the interaction between the receptor and intracellular signaling components is disrupted by a small molecule agent, using a single domain binder to prevent co-localization and allow reversible control of CAR signaling, thereby preventing unwanted toxic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If suicide genes are used to destroy CAR T-cells upon toxicity, then safety is improved, but the therapeutic window cannot be tuned and potency cannot be controlled
Solution Approach 1:
The patent applies dynamics by making the CAR signaling reversible through small molecule modulation. The CAR can be dynamically switched between active and inactive states by administering or withdrawing the small molecule, allowing real-time control of potency while maintaining safety. This resolves the contradiction by enabling both safety (through reversible shutdown) and adaptability (through tunable potency levels).
Solution Approach 2:
The patent changes the parameter of CAR signaling activity from binary (on/off via suicide gene) to continuous (tunable via small molecule concentration). By varying the concentration of the small molecule, the potency of CAR T-cells can be precisely controlled, while complete inhibition is achievable for safety. This resolves the contradiction between safety and potency control.
2Productivity
If CAR T-cells are autonomously proliferating, then therapeutic efficacy is improved, but toxicity becomes progressive and fulminant
Solution Approach 1:
The patent applies preliminary anti-action by incorporating a built-in safety mechanism that can preemptively or reactively inhibit CAR signaling before toxicity becomes fulminant. The small molecule provides a pre-positioned countermeasure that can be activated to oppose the harmful effects of autonomous proliferation, resolving the contradiction between efficacy and toxicity.
Solution Approach 2:
The patent implements feedback control where the small molecule acts as a feedback inhibitor that can be administered in response to observed toxicity or predicted risk. This creates a closed-loop system where therapeutic efficacy is maintained through autonomous proliferation, but toxicity is controlled through feedback-mediated inhibition, resolving the contradiction.
3Adaptability or versatility
If small molecule agents are used to disrupt CAR signaling, then reversible control is achieved, but additional complexity is introduced to the system
Solution Approach 1:
The patent uses a small molecule as an intermediary mediator between the clinician and the CAR T-cell system. Rather than directly modifying the CAR structure, the small molecule indirectly controls signaling by binding to the CAR complex. This adds minimal complexity while achieving reversible control, resolving the contradiction between adaptability and system complexity.
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 reversible and controllable termination of CAR signaling to avoid toxic effects, allowing for tuned potency and balanced therapeutic efficacy without eliminating CAR cells, reducing the risk of immunogenicity.
Implementation Method 1
a first binding domain which comprises a single domain binder which binds an agent
Implementation Method 2
a second binding domain which binds the single domain binder of the first binding domain of the receptor component
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) system comprising; (i) a receptor component comprising a antigen binding domain and a first binding domain; and (ii) a signalling component comprising a signalling domain and a second binding domain which binds the single domain binder of the first binding domain of the receptor component wherein either the first or second binding domains comprise a single domain binder, and wherein, binding of the first and second binding domains is disrupted by the presence of an agent, such that in the absence of the agent, the receptor component and the signalling component heterodimerize and binding of the antigen binding domain to antigen results in signalling through the signalling domain; whereas in the presence of the agent, the receptor component and the signalling component do not heterodimerize and binding of the antigen binding domain to antigen does not result in signalling through the signalling domain.