Switch Costimulatory Receptors for Tumor-Targeted T Cell Activation
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Solution Overview
Problem
Current approaches to prevent T cell inactivation by PD-1 or BTLA ligands, such as systemic treatment with antibodies, lead to autoimmunity and systemic inflammatory syndromes due to widespread inhibition of T cells within the tumor microenvironment and the entire immune system.
Innovation Solution
Development of a fusion protein comprising a first domain associated with a negative signal and a second domain associated with a positive signal, engineered into T cells to convert inhibitory signals into activating signals, enhancing immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic treatment with PD-1 or BTLA antagonistic antibodies is given to prevent T cell inactivation, then T cell activation is improved, but autoimmunity and systemic inflammatory syndromes occur
Solution Approach 1:
The fusion protein is designed with spatially separated functional domains: the first domain (negative signal) is positioned extracellularly to interact with PD-1 ligands in the tumor microenvironment, while the second domain (positive signal) is positioned intracellularly to provide activating signals. This local differentiation of signal functions allows targeted activation of T cells in the tumor microenvironment without system-wide effects, thereby preventing autoimmunity and systemic inflammatory syndromes while maintaining effective T cell activation against tumors.
2Reliability
If PD-1 or BTLA signal transduction is inhibited by small molecule compounds, then T cell inactivation is prevented, but the approach lacks specificity and may cause off-target effects
Solution Approach 1:
The fusion protein acts as an intermediary molecule that specifically mediates the conversion of inhibitory PD-1/BTLA signals into activating signals. The first domain binds to PD-1 ligands (PDL1/PDL2) with high specificity, while the second domain transduces this binding event as a positive signal through intracellular signaling pathways. This intermediary mechanism provides precise signal conversion at the molecular level, avoiding the non-specific effects associated with broad-spectrum small molecule inhibitors while effectively preventing T cell inactivation in the tumor microenvironment.
Data Source
AI summary
The present invention relates generally to a fusion protein that when displayed on a cell can convert a negative signal into a positive signal in the cell. The fusion protein is a chimeric protein in that the protein comprises at least two domains, wherein the first domain is a polypeptide that is associated with a negative signal and the second domain is a polypeptide that is associated with a positive signal. Thus, the invention encompasses switch receptors that are able to switch negative signals to positive signals for enhancement of an immune response.