Kinase Mutants for Selective Inhibitor Control of Engineered T-Cells
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current kinase inhibitors have a narrow spectrum of specificity, leading to ineffective treatment of diseases like cancer due to their limited affinity for wild-type kinases, and therapies using engineered T-cells can cause severe side effects and immune system shutdown.
Innovation Solution
Development of kinase mutants, such as ZAP-70 and Lck, sensitive to specific inhibitors with minimal affinity for wild-type kinases, allowing controlled modulation of engineered cell behavior for targeted disease treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kinase inhibitors are used to treat diseases, then disease treatment is achieved, but the inhibitors have narrow spectrum of specificity and limited affinity for wild-type kinases
Solution Approach 1:
The patent introduces specific point mutations at the gatekeeper position (and optionally secondary positions) of the target kinase to create localized structural changes in the active site. These localized modifications alter the binding pocket properties to accommodate specific inhibitor structures, thereby achieving high specificity for particular inhibitors while maintaining activity against the target kinase.
Solution Approach 2:
The patent systematically varies amino acid residues at specific positions (gatekeeper and secondary positions) to create a library of kinase mutants with different binding properties. By changing the chemical parameters (side chain size, charge, hydrophobicity) at these key positions, the patent optimizes the kinase-inhibitor interaction to achieve both high affinity and narrow specificity.
2Reliability
If engineered T-cells are used for therapy, then targeted disease treatment is achieved, but severe side effects and immune system shutdown occur
Solution Approach 1:
The patent introduces a controllable kinase mutant as an intermediary element in the T-cell therapy system. This mutant kinase serves as a molecular switch that can be selectively activated or inhibited to control T-cell activity. By using the mutant kinase as an intermediary, the patent enables precise temporal and spatial control of T-cell function, preventing uncontrolled activation and severe side effects while maintaining therapeutic efficacy.
3Ease of operation
If kinase mutants are developed for specific inhibitor sensitivity, then precise control of engineered cells is achieved, but the complexity of kinase engineering increases
Solution Approach 1:
The patent divides the kinase engineering task into manageable segments by focusing mutations on specific functional regions (gatekeeper position and secondary positions) rather than random mutagenesis throughout the entire kinase. This segmented approach to mutagenesis reduces the search space and simplifies the engineering process while achieving the desired specificity and control properties.
Data Source
AI summary
The present invention relates to methods of designing kinase mutants for reprogramming the sensitivity of a target kinase to some specific inhibitors, methods of reprogramming the sensitivity of a target kinase to some specific inhibitors, wherein those kinase inhibitors have little or no affinity for the wild-type target kinase, vectors or cells expressing said mutated kinases, composition and uses thereof for the prevention and/or treatment of a disease or disorder, in particular cancer.