Kinase Gatekeeper Mutants for Selective T-Cell Activity Switching
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 inability to target specific kinases, and adoptive cell therapy using engineered T-cells results in severe side effects and immune system shutdown.
Innovation Solution
Designing kinase mutants, such as ZAP-70 and Lck, to make them sensitive to specific inhibitors with little affinity for wild-type kinases, allowing controlled modulation of engineered cell behavior for targeted disease treatment and prevention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kinase inhibitors are used to treat diseases, then disease treatment is attempted, but the inhibitors have narrow spectrum of specificity and cannot target specific kinases effectively
Solution Approach 1:
The patent applies local quality by introducing specific mutations (e.g., M414A, M416Y) at particular positions in the kinase active site to create a modified binding pocket that selectively accommodates ATP analogs with high affinity, while maintaining normal ATP binding and kinase function. This localized modification enables specific kinases to be targeted by selected inhibitors without affecting other kinases.
Solution Approach 2:
The patent employs parameter changes by mutating the gatekeeper residue to alter the physical and chemical properties of the ATP-binding site, creating a novel pocket that changes the binding characteristics. This allows the mutated kinase to have high affinity for large ATP analogs while wild-type kinase does not bind these inhibitors, achieving selective inhibition.
2Reliability
If engineered T-cells are used in adoptive cell therapy, then cancer treatment is attempted, but severe side effects and immune system shutdown occur
Solution Approach 1:
The patent uses an intermediary approach by introducing a controllable switch mechanism through mutated kinases that can be selectively inhibited by specific ATP analogs. This allows external control of T-cell activity, enabling the therapy to be activated or deactivated as needed, thereby preventing uncontrolled immune responses and severe side effects while maintaining treatment efficacy.
Solution Approach 2:
The patent applies dynamics by creating T-cells with mutated kinases whose activity can be dynamically controlled through administration of specific inhibitors. The T-cell function can be turned on or off based on treatment requirements, allowing flexible control to maximize anti-tumor efficacy while minimizing harmful side effects and preventing immune system shutdown.
3Reliability
If gatekeeper mutation is introduced to sensitize kinase to ATP analogs, then specific inhibition is achieved, but extensive characterization and testing for pharmacokinetics is required
Solution Approach 1:
The patent applies universality by developing a platform technology where a set of standardized gatekeeper mutations can be applied to multiple different kinases to create a family of sensitized kinases. This modular approach allows the same inhibition strategy to be used across different kinase targets, reducing the need for extensive de novo characterization and testing for each individual kinase-inhibitor pair.
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.