Mutated HsADA2 Enzymes for Local Tumor Adenosine Degradation
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Solution Overview
Problem
Existing cancer treatments, particularly CAR-T cell therapies, are limited by the immunosuppressive tumor microenvironment due to high adenosine levels that inhibit immune cell function, and current methods to reduce adenosine levels are inadequate, as they either target specific enzymes with limited efficacy or diffuse throughout the body, requiring consistent dosing.
Innovation Solution
Engineering human adenosine deaminase 2 (HsADA2) enzymes with mutations at specific positions near the catalytic site to enhance catalytic activity, allowing them to be expressed and secreted by immune cells to directly degrade adenosine locally within tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If administered enzymes are used to degrade adenosine, then adenosine levels are reduced, but the enzymes diffuse throughout the body, preventing local impact and requiring consistent dosing
Solution Approach 1:
The patent applies local quality by engineering immune cells to express adenosine-degrading enzymes specifically at the tumor site, creating localized high concentrations of enzyme activity where it is needed most. This ensures potent local adenosine degradation without requiring systemic administration, allowing the therapy to act precisely where the immunosuppressive microenvironment exists while minimizing off-target effects and eliminating the need for frequent dosing.
2Quantity of substance
If current methods to reduce adenosine levels are used, then adenosine concentration is partially reduced, but they either target specific enzymes with limited efficacy or require consistent dosing throughout the body
Solution Approach 1:
The patent implements self-service by engineering immune cells to autonomously produce and secrete adenosine-degrading enzymes directly at the tumor microenvironment. These armed immune cells self-sustain the enzyme production locally, creating a self-reinforcing therapeutic effect that reliably reduces adenosine levels without requiring external dosing. The immune cells themselves become the source of the therapeutic agent, ensuring consistent and reliable adenosine degradation at the target site.
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
The mutated HsADA2 enzymes effectively reduce adenosine levels within tumors, enhancing the efficacy of immune cells by overcoming immunosuppression and improving tumor infiltration and activation.
Implementation Method 1
engineering human adenosine deaminase 2 (HsADA2) enzymes with mutations at specific positions near the catalytic site to enhance catalytic activity, allowing them to be expressed and secreted by immune cells to directly degrade adenosine locally within tumors
Data Source
AI summary
The invention is directed to mutants of adenosine deaminase 2 (ADA2) that have improved catalytic activity relative to wildtype ADA2, as well as compositions comprising the mutants and methods of using the mutants to treat various conditions.