METHODS AND COMPOSITIONS IN PROGRAMMABLE RECEPTOR FOR ANTIGEN DETECTION AND CUSTOMIZED CELL RESPONSES

METHODS AND COMPOSITIONS IN PROGRAMMABLE RECEPTOR FOR ANTIGEN DETECTION AND CUSTOMIZED CELL RESPONSES

Researchers at Stanford have developed new methods to create programmable synthetic receptors (PAGER).

The advent of programmable synthetic receptors represents a new era in cellular therapies and in biomedical science. There are currently tens of approved cellular therapies on the market today with several of those being cells that have been genetically modified in some capacity. Currently available methods for programmable synthetic receptors that can influence cell signaling and behavior in an antigen-dependent manner include Chimeric Antigen Receptors (CARs), synthetic Notch receptor (synnotch), and generalized extracellular molecule sensor (GEMS) receptors, among others. However, these receptors have innate caveats that limit their clinical use, including a lack of response to soluble antigens, lack of activation in response to specific protease cleavage, limited signaling outputs, and an inability to activate G protein signaling.

Stage of Research

The inventors have designed novel synthetic receptor fusion proteins that are highly versatile and programmable. These synthetic receptors can respond to one or more different input signals, including antigen binding or protease cleavage, and can generate multiple output signals. Briefly, these synthetic receptors are made up of an input module, a receptor module, and optionally an output molecule. One application of this concept is the PAGER system, which stands for Programmable Antigen-gated G-protein coupled Engineered Receptor. In this system, the G protein is the receptor module, while the input molecule includes a peptide inhibitor of a GPCR, an antigen binding molecule, and/or a linker which can contain a protease cleavage site. Once antigen binding or protease cleavage activates the receptor, it triggers a cascade of G protein mediated signaling within the target cell. Separately, this method can also enable programmable gene expression via protease specific cleavage of a protein recognition sequence. This in turn releases a transcription factor and activates transcription of a target gene. Overall, this method allows user-programmed input signals to activate gene expression or intracellular signaling pathways.

Applications

Programmable input signals that allow for the activation of gene expression or intracellular signaling pathways
Treatment of cancer, autoimmune diseases, and neurodegenerative disease with less toxicity for healthy cells, as compared to currently available methods

Advantages