Adapter CAR System for Soluble Antigen Recognition
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Solution Overview
Problem
Current CAR T cell therapies have limited success in treating solid tumors due to immune cell exhaustion, hostile tumor microenvironments, and lack of suitable surface antigens, making it challenging to effectively target and eliminate cancer cells.
Innovation Solution
Development of an adapter CAR system that allows immune cells to recognize and respond to soluble antigens in the tumor microenvironment through a non-covalent spacer molecule, enabling dimerization and activation of CARs, even in unstable systems, and allowing for localized and controlled immune cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a CAR system uses a non-covalent spacer molecule (adapter) to bind soluble antigens, then the immune cell can recognize and respond to soluble antigens in the tumor microenvironment, but the system becomes more unstable and less mechanically rigid
Solution Approach 1:
The patent introduces an adapter molecule as an intermediary component that bridges the CAR and the soluble antigen. The adapter has a first binding domain that binds to the CAR and a second binding domain that binds to the soluble antigen, enabling indirect recognition while maintaining system stability through the mediator structure
Solution Approach 2:
The CAR system is constructed as a composite structure comprising multiple functional domains: an antigen binding domain (scFv), a transmembrane domain, and an intracellular signaling domain. This composite architecture allows the system to integrate multiple functions (binding, membrane anchoring, signaling) while maintaining overall stability despite the non-covalent adapter connection
2Strength
If the CAR binding affinity is increased to withstand tensile force for activation, then the CAR can be triggered by soluble ligands, but the system may become too rigid to allow flexible adapter binding
Solution Approach 1:
The binding interaction is segmented into two separate binding events: the adapter binds to the CAR with one binding domain, and the adapter simultaneously binds to the soluble antigen with another binding domain. This segmentation allows each binding interface to be optimized independently for its specific function
Solution Approach 2:
The adapter serves as a flexible mediator that can accommodate different binding geometries and affinities at its two ends, allowing the system to achieve strong overall binding while maintaining flexibility in the adapter-CAR interaction
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 adapter CAR system effectively activates immune cells to recognize and target soluble antigens, leading to enhanced cytolytic activity and localized inflammation, improving the efficacy of CAR T cell therapy for solid tumors by allowing immune cells to selectively target tumor-associated antigens.
Implementation Method 1
The essential requirement for the activation of the immune cell expressing the adapter CAR is the soluble antigen mediated dimerization of the adapter CAR
Implementation Method 2
both the soluble ligand and the CARs involved must be mechanically rigid enough to transmit tensile force to the CARs' intracellular signaling domains
Implementation Method 3
the use of an additional, non-covalent bound spacer molecule, i.e. the adapter, is inserted between the antigen and the CAR expressed on the surface of the immune cell
Data Source
AI summary
The present invention provides a composition comprising a) an immune cell comprising a polynucleotide encoding an adapter CAR specific for an adapter, b) the adapter specific for a soluble antigen, and c) the soluble antigen. In an embodiment of the invention, the immune cell expressing said adapter CAR comprises in addition a nucleic acid comprising an inducible promoter operably linked to a nucleic acid encoding an effector such as a synthetic.