CD123 Targeting Modules With La Epitope E5B9 Tag Binding
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Solution Overview
Problem
Conventional CAR technology faces challenges such as uncontrolled immune responses, tumor escape variants, and restricted retargeting to a single antigen, limiting its clinical applications.
Innovation Solution
A targeting module comprising a CD123-binding domain and a tag-binding domain that binds to the human La epitope E5B9, specifically designed for use in a RevCAR system, allowing flexible antigen recognition and minimizing off-site toxicities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional CAR technology is used to target a single antigen, then the immune response is focused and controllable, but the risk of tumor escape variants increases and retargeting flexibility is restricted
Solution Approach 1:
The CAR system is divided into two independent components: a universal CAR expressing a constant tag (e.g., La epitope) and interchangeable targeting modules. Each targeting module contains a variable antigen-binding domain (e.g., scFv) and a constant tag-binding domain. This segmentation allows the targeting module to be exchanged without modifying the universal CAR, enabling retargeting to different antigens while maintaining controlled immune responses through the universal CAR design.
Solution Approach 2:
The universal CAR is designed with a constant tag (e.g., La epitope from human La protein) that can bind to multiple different targeting modules. This universal CAR can recognize various antigens by simply exchanging the targeting module, providing multi-functionality. The universal CAR structure remains unchanged, ensuring consistent and controlled immune response characteristics across different targeting applications.
2Power
If CAR-T cells are engineered to express high levels of activation markers, then the immune response potency is enhanced, but the risk of cytokine release syndrome and macrophage activation syndrome increases
Solution Approach 1:
The system enables dynamic control of CAR-T cell activation through the reversible binding interaction between the universal CAR tag and the targeting module. The CAR-T cells remain in an inactive state when no targeting module is present, and can be selectively activated only when the targeting module is introduced. This dynamic on/off control allows potent immune responses to be triggered only when needed, reducing the risk of uncontrolled cytokine release and macrophage activation.
3Measurement precision
If the CAR binding domain is designed for high affinity binding, then the antigen recognition efficiency is improved, but the off-site toxicities against normal tissues increase
Solution Approach 1:
The targeting module acts as an intermediary between the universal CAR and the antigen. The universal CAR binds to the constant tag on the targeting module with high affinity, while the variable antigen-binding domain on the targeting module provides antigen specificity. This intermediary design allows the system to achieve high antigen recognition efficiency through the combined affinity of CAR-tag binding and targeting module-antigen binding, while the modular structure enables precise control to minimize off-site toxicities by selecting appropriate targeting modules with optimized antigen specificity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enhances the flexibility of CAR therapy by enabling targeting of multiple antigens while reducing the risk of cytokine storms and tumor escape variants, thereby expanding its therapeutic potential.
Implementation Method 1
A targeting module comprising at least one CD123-binding domain and a tag-binding domain binding the human La epitope E5B9
Data Source
AI summary
The present invention relates to a targeting module comprising at least one CD123-binding domain and a tag-binding domain binding the human La epitope E5B9, a nucleic acid, a vector or a cell comprising a nucleotide sequence encoding the targeting module, a pharmaceutical composition and a kit comprising the targeting module and a vector or a cell comprising a nucleotide sequence encoding a reversible chimeric antigen receptor.