CAR Binding Kinetics for Stronger Serial Cancer Cell Killing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing CAR T-cell therapies often fail to effectively serially kill cancer cells due to T-cell exhaustion and differentiation during production, despite optimization efforts.
Innovation Solution
Development of a chimeric antigen receptor (CAR) with an antigen-binding domain having a fast on-rate and a fast off-rate, characterized by an affinity in the range of 50 nM to 500 nM, with association and dissociation rate constants of 1×105 M−1 s−1 to 1×107 M−1 s−1 and 0.01 s−1 to 0.5 s−1, respectively, to enhance the serial killing capability of T-cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T-cells are generated through selective expansion of peripheral blood T-cells, then T-cell specificity for target antigen is achieved, but the process is difficult and often impossible to select and expand large numbers of T-cells
Solution Approach 1:
The patent applies the copying principle by using gene therapy with integrating vectors to create transgenic expression of Chimeric Antigen Receptor (CAR). Instead of selecting and expanding rare native T-cells, the invention copies the desired antigen specificity by introducing the CAR gene into bulk peripheral blood T-cells, enabling generation of large numbers of T-cells with the required specificity.
Solution Approach 2:
The patent replaces the mechanical selection and expansion process with a genetic engineering approach. Rather than physically selecting and expanding T-cells based on their antigen specificity, the invention uses viral vector transduction to introduce the CAR gene, substituting the mechanical selection process with a genetic modification approach that achieves both specificity and scalability.
2Productivity
If CAR T-cells are generated using gene-therapy with integrating vectors, then large numbers of T-cells specific to any surface antigen can be generated, but T-cell exhaustion and differentiation occur during production
Solution Approach 1:
The patent applies preliminary action by implementing optimized CAR T-cell manufacturing processes that prevent exhaustion and differentiation during production. The invention performs necessary preparatory steps during the manufacturing phase to ensure T-cells remain functional and ready for therapeutic use, addressing the exhaustion issue before it can compromise T-cell effectiveness.
3Reliability
If CAR T-cells are optimized for manufacturing processes to prevent exhaustion, then T-cell functionality is improved, but CAR T-cells still fail to function effectively in serial killing
Solution Approach 1:
The patent applies parameter changes by optimizing the binding kinetics parameters of the CAR antigen-binding domain. The invention specifically adjusts the association rate constant (kon) to be greater than or equal to 1×10^5 M^-1 s^-1 and the dissociation rate constant (koff) to be greater than or equal to 0.01 s^-1, which significantly enhances the serial killing capability of CAR T-cells while maintaining their functionality.
4Ease of manufacture
If CAR T-cells use traditional antigen-binding domains, then manufacturing is simpler, but serial killing efficiency is insufficient
Solution Approach 1:
The patent applies parameter changes to the binding kinetics of the antigen-binding domain, adjusting kon and koff values to achieve superior serial killing efficiency. This optimization of kinetic parameters enhances the functional performance of CAR T-cells while maintaining the overall simplicity of the CAR structure and manufacturing process.
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) comprising an antigen-binding domain with an affinity in the range of 50 nM to 500 nM, wherein said affinity comprises component kinetics such that the association rate constant (kon) is greater than or equal to 1×105 M−1 S−1, and/or the dissociation rate constant (koff) is greater than or equal to 0.01 s−1.