Switchable CAR-T Cell Fusion Polypeptide Modulation
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in maintaining long-term disease remission due to poor maintenance of CAR-T cell function and the emergence of resistant cancer cells, along with off-target activity and toxicity, necessitating a method to specifically modulate the activity of CAR-T cells post-infusion.
Innovation Solution
Development of fusion polypeptides that selectively bind to CAR-expressing cells, utilizing a targeting moiety to recognize a specific epitope on the CAR and an additional moiety to deliver costimulatory or inhibitory signals, such as CD28 or 4-1BBL, to modulate CAR-T cell function in vivo or ex vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are engineered with costimulatory signaling domains to enhance therapeutic activity, then the ability to eliminate malignant cells is improved, but off-target activity and toxicity increase
Solution Approach 1:
The patent introduces a switchable CAR-T cell system where the costimulatory signaling domain can be dynamically activated or deactivated. The CAR construct includes a switching module that allows control over the costimulatory domain's activity state, enabling the system to adapt between high-activity (therapeutic) and low-activity (safe) modes as needed clinically.
Solution Approach 2:
The patent employs an intermediary switching mechanism that mediates between the antigen recognition function and the costimulatory signaling function. This switching module acts as a controllable intermediary that can selectively enable or disable the costimulatory signals, thereby controlling the overall therapeutic activity and toxicity profile of the CAR-T cells.
2Reliability
If CAR-T cell activity is enhanced to improve cancer elimination, then disease remission capability is improved, but maintenance of CAR-T cell function deteriorates
Solution Approach 1:
The switchable CAR-T cell system allows dynamic control over CAR-T cell activity states. By temporarily activating costimulatory signals during therapy and then deactivating them, the system can achieve strong initial anti-tumor effects while reducing long-term functional exhaustion and maintaining sustained CAR-T cell persistence in the body.
Solution Approach 2:
The patent enables periodic activation and deactivation of CAR-T cell costimulatory functions. This periodic control allows the system to deliver intense therapeutic pulses when needed while providing rest periods that prevent cellular exhaustion, thereby maintaining long-term CAR-T cell functionality and disease remission.
3Ease of manufacture
If current CAR construct design is used with limited costimulatory domains, then manufacturing simplicity is maintained, but modulation flexibility of CAR-T cell function deteriorates
Solution Approach 1:
The patent segments the CAR construct into modular components: an antigen recognition domain, a switching module, and a costimulatory signaling domain. This segmentation allows the costimulatory function to be independently controlled and switched, providing modulation flexibility while maintaining a relatively simple overall construct design that can be manufactured using standard viral vector systems.
Solution Approach 2:
The switching module design provides universal control capability that can regulate different costimulatory domains (such as CD28, 4-1BB, or other costimulatory receptors). This multi-functional switching mechanism allows a single CAR construct design to accommodate various costimulatory configurations, enhancing versatility without significantly complicating the manufacturing process.
Data Source
AI summary
Polypeptides, nucleic acids, and compositions thereof are provided that include a targeting moiety. The polypeptides, nucleic acids, and compositions that comprise them, can be used in methods to treat subjects, to alter CAR-expressing cells in subjects who may suffer from a disease such as a cancer or a pathogen.