Chimeric Switch Receptors Using IL-9 Endodomain for Immune Control
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Solution Overview
Problem
Current methods for manipulating immune cells, such as in adoptive immunotherapy, face challenges in selectively activating signaling in targeted cell populations without affecting non-targeted cells, and in preventing negative signals that can lead to autoimmunity or systemic inflammatory syndrome.
Innovation Solution
The development of chimeric switch receptors with an IL-9 endodomain that can be modulated by extracellular ligands, allowing for spatial and temporal control of gene expression and immune cell activity, and the use of recombinant nucleic acids encoding these receptors to engineer immune cells for therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If cytokines and chemokines are used to manipulate immune cell differentiation and expansion, then cell activities can be modulated, but pleiotropic effects on non-targeted cells occur
Solution Approach 1:
The receptor is divided into modular components: an extracellular ligand-binding domain specific to the target cell type, a transmembrane domain, and an intracellular signaling domain (IL-9 endodomain). This segmentation allows the receptor to be activated only when the specific ligand binds to the extracellular domain on the target cell, preventing off-target effects on non-targeted cells while maintaining the desired immune cell manipulation capabilities.
2Adaptability or versatility
If orthogonal cytokine-receptor pairs are engineered for selective manipulation, then targeted cell population control is achieved, but finding mutations that prevent endogenous activation without compromising receptor structure is challenging
Solution Approach 1:
The patent introduces a chimeric receptor that acts as an intermediary between the extracellular ligand and the intracellular signaling pathway. The receptor's extracellular domain is engineered to bind the ligand with high specificity, while the intracellular IL-9 endodomain domain transmits the signal selectively. This intermediary structure allows controlled activation only in cells expressing the engineered receptor, avoiding unwanted activation by endogenous molecules and simplifying the generation of orthogonal pairs.
3Reliability
If systemic treatment with antagonistic antibodies is used to prevent negative signals from PD-1, then T cell inactivation is blocked, but autoimmunity or systemic inflammatory syndrome can occur
Solution Approach 1:
Instead of systemic treatment with antagonistic antibodies that affect the entire immune system, the patent employs locally expressed chimeric receptors on specific immune cells. The extracellular domain of the receptor is designed to bind ligands with high local concentration at the tumor microenvironment, enabling selective prevention of T cell inactivation only where needed. This localized approach maintains T cell functionality in the tumor microenvironment without causing systemic autoimmune responses or inflammatory syndrome.
Data Source
AI summary
The present disclosure generally relates to, inter alia, a class of chimeric switch receptors containing an endodomain of an IL-9 receptor, engineered to modulate transcriptional regulation in a ligand-dependent manner. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating gene expression, modulating an activity of a cell, and/or for the treatment of various health conditions or diseases.