Switch Molecule for Controlling CAR-T Cell Activation
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Solution Overview
Problem
Conventional CAR-T cells lack control over activation and expansion in vivo, leading to severe toxicity and persistent on-target activity, and are limited by fixed antigen-specificity, which precludes targeting of antigen-loss escape mutants, resulting in treatment failures and relapse in cancer therapy.
Innovation Solution
A switch molecule comprising a targeting moiety binding to a cell surface molecule on target cells and a polypeptide binding to a chimeric antigen receptor on effector cells, allowing for controlled activation and interaction, enhancing safety and adaptability to antigen mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cells are used to target cancer cells, then cancer cells are eliminated, but severe toxicity and persistent on-target activity occur
Solution Approach 1:
The patent applies dynamics by making the CAR-T cell activation state changeable through switch molecules. The CAR-T cell transitions from an inactive state to an active state upon binding the switch molecule, allowing controlled activation only when needed. This dynamic control mechanism resolves the contradiction by enabling cancer cell elimination when required while preventing unwanted toxicity through conditional activation.
Solution Approach 2:
The switch molecule serves as an intermediary between the CAR-T cell and the target cancer cell. Instead of direct contact triggering activation, the switch molecule mediates the interaction by first binding to the CAR-T cell's extracellular domain, then facilitating targeted engagement with cancer cells. This intermediary mechanism allows precise control over CAR-T cell activation and reduces harmful off-target effects.
2Productivity
If CAR-T cells undergo rapid proliferation to eliminate cancer, then cancer is treated effectively, but tumor lysis syndrome and cytokine release syndrome occur
Solution Approach 1:
The patent implements periodic action through temporal control of CAR-T cell activation. The switch molecule is administered only when activation is needed, creating discrete activation episodes rather than continuous proliferation. This periodic activation pattern allows effective cancer treatment while preventing sustained cytokine release and tumor lysis syndrome associated with uncontrolled continuous proliferation.
3Reliability
If CAR-T cells have fixed antigen-specificity, then consistent targeting is achieved, but antigen-loss escape mutants cannot be targeted
Solution Approach 1:
The patent applies dynamics by making the CAR-T cell's antigen recognition capability changeable through switch molecule binding. Before activation, the CAR-T cell exists in an inactive state that can be dynamically changed to an active state with functional antigen recognition. This dynamic transition enables the system to adapt to different antigenic conditions while maintaining consistent targeting behavior when activated, resolving the contradiction between fixed specificity and adaptability.
Data Source
AI summary
The present invention relates to a switch molecule for activating a chimeric antigen receptor effector cell, to a polypeptide or fusion protein binding thereto, and to a chimeric antigen receptor. (i) When a switch molecule of the present invention is used, in order to improve safety of a CAR-T cell, if severe toxicity appears, a switch molecule lacking a targeting moiety can be injected to adjust activation of the CAR-T cell. (ii) When an antigen is mutated, or in order to cure various carcinomas, instead of an existing switch molecule, a switch molecule targeting a new antigen generated due to the mutation or a switch molecule targeting a different tumor associated antigen (TAA) can be injected into a patient to cure cancer more effectively.