Inhibitory CARs with ITSM motifs for T-cell safety
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Solution Overview
Problem
Current CAR T-cell therapies face challenges with on-target off-tissue activity, leading to safety concerns and reduced efficacy due to the inability to effectively differentiate between tumor and non-tumor antigens, necessitating the development of logic gates to modulate T-cell signaling.
Innovation Solution
The use of negative chimeric antigen receptors (N-CARs) that provide a short-term, reversible negative signal to attenuate T-cell activation when binding to off-tumor antigens, in conjunction with positive chimeric antigen receptors (P-CARs) for tumor targeting, to prevent off-target activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T-cells are used to target tumor antigens, then anti-tumor efficacy is improved, but on-target off-tissue activity causes safety concerns and tissue damage
Solution Approach 1:
The patent divides the CAR T-cell system into two distinct functional components: P-CARs (positive CARs) that provide activating signals for tumor killing, and N-CARs (negative CARs) that provide inhibitory signals to prevent off-target activity. This segmentation allows independent optimization of efficacy and safety functions.
Solution Approach 2:
The N-CAR acts as an intermediary safety mechanism that monitors antigen expression contexts. When N-CAR binds to antigens in non-tumor contexts, it mediates an inhibitory signal that prevents P-CAR activation, thereby protecting healthy tissues while allowing tumor targeting.
2Object-affected harmful factors
If N-CARs are introduced to prevent off-target activity, then safety is improved, but T-cell activation and proliferation may be attenuated
Solution Approach 1:
The inhibitory N-CAR signal is designed to be context-dependent, acting locally only in non-tumor environments where the specific antigen pattern is recognized. In tumor contexts, the absence or different expression pattern of target antigens allows P-CAR signaling to dominate, ensuring full T-cell activation power where needed.
Solution Approach 2:
The N-CAR provides preliminary inhibitory action that prevents activation only when appropriate safety conditions are met (i.e., when binding to off-target antigens). This preliminary check occurs before full T-cell activation, allowing safety verification without permanently suppressing T-cell potential.
3Object-affected harmful factors
If dual CAR expression is used to create logic gates, then safety control is improved, but device complexity increases
Solution Approach 1:
The patent merges the safety function into the CAR structure itself by creating N-CAR variants with inhibitory intracellular domains (such as ITIM or ITSM motifs). This combines the antigen recognition and safety signaling functions into a single receptor unit, reducing the need for separate regulatory components.
Solution Approach 2:
The N-CAR design provides multi-functionality by simultaneously serving as an antigen recognition molecule and a safety regulatory mechanism. The same N-CAR structure that binds to antigens also provides the inhibitory signal, eliminating the need for separate safety monitoring systems.
Data Source
AI summary
The invention relates to an inhibitory chimeric antigen receptor (N-CAR) comprisingan extracellular domain comprising an antigen binding domain,a transmembrane domain and,an intracellular domainwherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX1YX2X3X4, whereinX1 is an amino acidX2 is an amino acidX3 is an amino acid andX4 is V or I.