CAR-T Cells with Catalytic Antibody Adapters
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Solution Overview
Problem
Current CAR-T therapy for treating chronic lymphocytic leukemia (CLL) is limited by the induction of Cytokine Release Syndrome (CRS) and on-target off-tumor effects due to the overactivation of T cells.
Innovation Solution
Development of chimeric antigen receptor T (CAR-T) cell compositions that incorporate a catalytic antibody in the extracellular domain of the CAR and an adapter compound with a substrate moiety linked to a targeting moiety, allowing for controlled targeting of tumor cells through covalent bond formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T therapy is used to treat chronic lymphocytic leukemia, then remission rates are improved, but Cytokine Release Syndrome and on-target off-tumor effects are induced due to overactivation of T cells
Solution Approach 1:
The patent introduces an adapter molecule as an intermediary between the CAR-T cell and the target antigen. The adapter consists of a targeting moiety that binds to the tumor antigen and a substrate moiety that forms a covalent bond with the catalytic antibody. This intermediary controls the activation of CAR-T cells, allowing them to be activated only when the adapter is present, thereby reducing uncontrolled overactivation and associated harmful effects while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs a small molecule adapter that can be administered at controlled dosages to regulate CAR-T cell activity. By changing the concentration and timing of adapter administration, the therapeutic effect can be modulated - low doses provide controlled activation for tumor killing while avoiding excessive activation that leads to CRS and off-tumor effects
2Ease of operation
If small molecule activators or antibody adapters are used to control CAR-T cell activity, then controlled activation is achieved, but device complexity increases
Solution Approach 1:
The adapter molecule is segmented into two functional parts: a targeting moiety that recognizes the tumor antigen and a substrate moiety that interacts with the catalytic antibody on the CAR-T cell. This segmentation allows each part to perform its specific function independently - the targeting moiety provides specificity while the substrate moiety enables controlled activation through covalent bond formation
Solution Approach 2:
The adapter molecule is a composite structure combining a small molecule targeting agent with a catalytic antibody substrate. This composite design integrates the targeting capability of small molecules with the catalytic activation mechanism, creating a unified control mechanism that simplifies the overall system while maintaining controlled activation
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
The approach enables precise targeting of tumor cells with reduced off-target effects and improved control over CAR-T cell activity, potentially enhancing the therapeutic efficacy and safety of CAR-T therapy.
Implementation Method 1
the catalytic antibody is capable of catalyzing formation of a covalent bond between the antibody and the substrate moiety
Data Source
AI summary
The invention provides chimeric antigen receptor T (CAR-T) cell compositions for targeting tumor cells. The compositions contain (a) a CAR-T cell having in the extracellular domain of its CAR a catalytic antibody (e.g., a scFv molecule derived from catalytic antibody 38C2), and (b) an adapter compound containing a substrate moiety of the catalytic antibody that is linked to a targeting moiety that specifically recognizes a surface molecule of a target tumor cell. The compositions allow formation of a covalent bond between the catalytic antibody in the CAR and the targeting moiety. The targeting moieties employed in the compositions can be obtained via screening DNA-encoded compound library for specific binding to the target tumor surface molecules. Also provided in the invention are therapeutic methods of using the CAR-T cell compositions of the invention to in the treatment of various tumors of interest.