Engineered Immune Cells for Localized Prodrug Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing adoptive cell therapies, such as CAR T cells and TCR T cells, face challenges with resistance, relapse, toxicity, and graft versus host disease (GVHD), necessitating improved methods to enhance efficacy and control.
Innovation Solution
Engineered immune cells expressing a prodrug converting enzyme and a receptor that binds to a target antigen, allowing for localized activation of prodrugs to active drugs at sites of inflammation or infection, using enzymes like Pseudomonas sp. Carboxypeptidase G2 (CPG2) or Enterobacter cloacae β-lactamase, and chimeric antigen receptors (CARs) for targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If prodrugs are administered systemically to treat diseases, then therapeutic coverage is improved, but off-target toxicity increases
Solution Approach 1:
The patent applies local quality by making the prodrug converting enzyme (such as CPG2 or β-lactamase) specific to engineered immune cells, which then accumulate at disease sites. This ensures the active drug is generated only locally at the target site (tumor, infection, or inflammation) rather than systemically throughout the body, thereby maintaining therapeutic coverage while minimizing off-target toxicity to healthy tissues
Solution Approach 2:
The patent uses an intermediary approach by introducing a prodrug converting enzyme as a mediator between the administered prodrug and the active therapeutic drug. The engineered immune cells express this enzyme, which converts the inactive prodrug to the active drug only in the vicinity of the target disease site, acting as a localized intermediary that enables therapeutic action without systemic exposure
2Measurement precision
If engineered immune cells are used for targeted therapy, then specificity is improved, but device complexity increases
Solution Approach 1:
The patent applies universality by designing engineered immune cells that simultaneously perform multiple functions: (1) expressing a receptor for target recognition and binding, (2) expressing a prodrug converting enzyme for localized drug activation, and (3) providing therapeutic action. This multi-functional approach achieves high targeting specificity while consolidating multiple therapeutic mechanisms into a single cell type
Solution Approach 2:
The patent uses composite materials by creating engineered immune cells that are composite biological entities combining different functional components: a receptor protein for antigen recognition, a prodrug converting enzyme (such as CPG2 or β-lactamase) for drug activation, and the immune cell's inherent therapeutic capabilities. This composite structure enables precise targeting and controlled drug activation
3Reliability
If second generation CARs with costimulation are used, then T cell activation is improved, but toxicity increases
Solution Approach 1:
The patent applies the extraction principle by separating the drug activation function from the T cell activation function. The prodrug converting enzyme is expressed independently on the immune cell surface, allowing T cell activation through receptor engagement while drug activation occurs separately through the enzyme's catalytic activity, thereby reducing the toxicity associated with systemic drug delivery
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 therapeutic efficacy by enabling precise targeting and activation of prodrugs at specific sites, reducing off-target effects and toxicity, and providing effective treatments for inflammation, autoimmune diseases, and pathogenic infections.
Implementation Method 1
engineered immune cells that express a prodrug converting enzyme and a receptor that binds to a target antigen
Data Source
AI summary
Provided herein are compositions and methods for adoptive cell therapy comprising engineered immune cells that express an antigen-targeted chimeric antigen receptor and a prodrug converting enzyme for the treatment of inflammation, inflammatory diseases, or pathogenic infections.