CAR Hinge, Transmembrane, and Intracellular Modifications for T Cell Function
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for T cell therapies are limited in their ability to effectively target and kill cancer cells, necessitating improved designs to enhance T cell functionality.
Innovation Solution
Introduction of amino acid modifications in the hinge, transmembrane, and intracellular domains of CARs to modulate their activity, including alterations such as leucine zippers, salt bridges, and glycosylation states, which affect oligomerization propensity and surface association.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amino acid modifications are introduced in the hinge, transmembrane, or intracellular domains of CARs, then the functional properties of CAR T cells (proliferation, cytokine production, targeting capability) are enhanced, but the structural complexity of the CAR increases
Solution Approach 1:
The patent applies local quality by making specific amino acid modifications at particular locations within the CAR structure (hinge domain, transmembrane domain, intracellular domain). Each domain receives targeted modifications tailored to its specific function - the hinge domain modifications optimize oligomerization and surface association, transmembrane domain modifications stabilize membrane integration, and intracellular domain modifications enhance signaling. This localized approach improves CAR T cell functionality without requiring complete redesign of the entire CAR structure.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at specific positions within the CAR domains. Modifications include introducing leucine zipper motifs, creating salt bridges, altering glycosylation states, and changing hydrophobicity parameters. These parameter changes in amino acid composition directly modulate CAR oligomerization propensity, surface association, and downstream signaling, thereby enhancing CAR T cell proliferation, cytokine production, and cancer cell killing capabilities.
2Reliability
If amino acid modifications are introduced to modulate CAR activity, then cancer cell targeting and killing capabilities are improved, but the difficulty of manufacturing precise modifications increases
Solution Approach 1:
The patent applies segmentation by dividing the CAR into distinct functional domains (extracellular domain, hinge domain, transmembrane domain, intracellular domain) and addressing modifications separately in each segment. This modular approach allows independent optimization of each domain's properties - the hinge domain can be modified to control oligomerization, the transmembrane domain to stabilize membrane integration, and the intracellular domain to enhance signaling. This segmentation simplifies the manufacturing process by allowing standardized modification protocols for each domain rather than requiring complex global redesign.
Solution Approach 2:
The patent employs preliminary action by pre-defining the optimal amino acid sequences and modification sites before actual CAR manufacturing. The hinge domain modifications (such as introducing leucine zipper motifs or creating salt bridges) are designed in advance based on computational modeling and structural analysis. This preliminary design phase identifies the precise modification sites and sequences needed to achieve desired oligomerization states and surface association, allowing for standardized, reproducible manufacturing processes that maintain high targeting precision without requiring complex real-time adjustments.
Data Source
AI summary
The disclosure provides a chimeric antigen receptor (CAR) comprising a modified hinge, transmembrane and/or intracellular domain disclosed herein. Some aspects of the disclosure relate to a polynucleotide encoding a chimeric antigen receptor (CAR) comprising the costimulatory domain disclosed herein. Other aspects of the disclosure relate to cells comprising the CAR and use in a T cell therapy.