In-series Synthetic Receptor Circuits for CAR T Cell Specificity
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Solution Overview
Problem
Current CAR T cell therapies for cancer are limited by the lack of specific antigen targets, leading to on-target off-tumor cross-reactions due to the similarity between cancer and normal cell molecular features, particularly in solid tumors, where single antigen targeting is insufficient for discrimination.
Innovation Solution
An in-series synthetic receptor circuit for dual-antigen AND-gate control over therapeutic payload expression in engineered cells, utilizing a first binding-triggered transcriptional switch to activate a second switch, which then activates a chimeric antigen receptor upon binding to a third antigen, requiring multiple antigens for activation to minimize off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single antigen targeting is used in CAR T cell therapies, then the therapy can be implemented with simpler design and lower complexity, but it leads to on-target off-tumor cross-reactions and insufficient discrimination between cancer and normal cells
Solution Approach 1:
The patent segments the antigen recognition function into multiple independent synNotch receptors, each recognizing a different antigen. Instead of using a single receptor that targets one antigen, the system divides the recognition task across multiple receptors (e.g., synNotch1 recognizing Antigen1, synNotch2 recognizing Antigen2) that work in series. This segmentation enables the T cell to discriminate cancer cells from normal cells by requiring the presence of multiple antigens simultaneously, thereby improving specificity while managing complexity through modular design
Solution Approach 2:
The patent transitions from single-antigen recognition (one-dimensional) to multi-antigen recognition (multi-dimensional) by implementing an in-series synthetic receptor circuit. The circuit requires sequential activation through multiple antigen recognition events, adding dimensional complexity to the recognition process. This dimensional expansion allows the system to differentiate between cancer cells (expressing multiple antigens) and normal cells (expressing fewer or different antigen combinations), resolving the contradiction between specificity and complexity
2Object-affected harmful factors
If multiple antigens are required for activation to improve specificity, then off-tumor toxicities are reduced, but the circuit complexity increases with multiple binding-triggered transcriptional switches
Solution Approach 1:
The patent segments the therapeutic function into modular components: multiple synNotch receptors (each with its own binding-triggered transcriptional switch) that recognize different antigens, connected in series to control the expression of a single therapeutic payload. This segmentation allows the system to require multiple antigen recognitions (reducing off-tumor toxicities) while organizing the complexity into manageable, independent modules that can be engineered and regulated separately
Solution Approach 2:
The patent introduces binding-triggered transcriptional switches as intermediary elements between antigen recognition and therapeutic payload expression. These transcriptional switches act as mediators that translate the binding events of multiple synNotch receptors into coordinated gene expression. The intermediaries buffer the complexity by providing a regulatory layer that integrates multiple signals before activating the therapeutic function, thereby reducing off-tumor toxicities while managing circuit complexity
3Measurement precision
If combinatorial antigen pattern recognition is implemented, then cancer cell targeting specificity is significantly improved, but the options for engineering mammalian cells with these capabilities are currently limited
Solution Approach 1:
The patent creates a universal platform for combinatorial antigen pattern recognition using synNotch receptors with binding-triggered transcriptional switches. This platform is highly adaptable and can be configured to recognize different combinations of antigens by simply changing the extracellular binding domains of the synNotch receptors. The in-series circuit architecture serves as a universal framework that can be applied to various cancer types and antigen targets, significantly improving cancer cell discrimination precision while expanding the versatility of cell engineering options through modular reconfigurability
Data Source
AI summary
Provided herein is an in-series synthetic receptor circuit for dual-antigen AND-gate control over expression of a therapeutic payload by engineered cells. In some embodiments, the circuit may be composed of a first binding-triggered transcriptional switch, a second binding-triggered transcriptional switch and a therapeutic payload (e.g., a chimeric antigen receptor), where binding of the first binding-triggered transcriptional switch to a first antigen activates expression of the second binding-triggered transcriptional switch, and binding of the second binding-triggered transcriptional switch to a second antigen activates expression of the therapeutic payload. If the cell is an immune cell and the therapeutic payload is a chimeric antigen receptor, then the immune cell may be activated by binding of the chimeric antigen receptor to a third antigen. Methods of treatment using the cell also provided.