Chimeric Polypeptide Protease Activation for Targeted IL-2 Delivery
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Solution Overview
Problem
Current treatments for diseases and infections often require systemic administration of active agents, leading to toxic side effects due to higher doses, and local administration is not always feasible due to invasive procedures or poorly defined target locations.
Innovation Solution
Development of chimeric nucleic acid sequences and polypeptides that include an interleukin-2 (IL-2) cytokine, a protease-cleavable amino acid sequence, and a blocking polypeptide, allowing for targeted and controlled release of IL-2 at the site of infection or cancer through protease activation, enhancing local bioactivity while minimizing systemic side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If systemic administration of active agents is used to treat diseases and infections, then treatment coverage is improved, but toxic side effects increase due to higher doses
Solution Approach 1:
The patent applies local quality by designing a chimeric polypeptide where the IL-2 cytokine is fused to a protease-cleavable sequence and a blocking polypeptide. The blocking polypeptide locally inhibits IL-2 activity in circulation, while the protease-cleavable sequence enables local activation at the target site by host proteases, creating high IL-2 concentration only where needed rather than systemic distribution
Solution Approach 2:
The patent uses the blocking polypeptide as an intermediary that temporarily prevents IL-2 from binding to its receptor. This intermediary blocks systemic IL-2 activity but can be removed by proteolytic cleavage at the target site, allowing controlled local activation without requiring direct systemic administration of active IL-2
2Object-affected harmful factors
If local administration of active agents is used to reduce side effects, then systemic toxicity is decreased, but feasibility is reduced due to invasive procedures or poorly defined target locations
Solution Approach 1:
The chimeric polypeptide is designed to self-activate at the target site through proteolytic cleavage by host proteases that are naturally present at sites of inflammation or infection. This eliminates the need for invasive local administration procedures, as the drug automatically activates itself at the correct location based on the presence of specific proteases
Solution Approach 2:
The patent changes the molecular state of the IL-2 cytokine from an inactive blocked form to an active form through proteolytic cleavage. This parameter change (from blocked to unblocked) is triggered by the presence of specific proteases at the target site, enabling automatic localization without invasive procedures
3Object-affected harmful factors
If chimeric polypeptides with blocking polypeptides are used, then systemic side effects are reduced, but device complexity increases due to multiple polypeptide components
Solution Approach 1:
The patent merges multiple functional components into a single chimeric polypeptide molecule: the IL-2 cytokine, the protease-cleavable sequence, and the blocking polypeptide are all fused together. This single merged molecule performs multiple functions (systemic blocking, local activation, immune stimulation) that would otherwise require separate components or procedures
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 chimeric polypeptides effectively increase IL-2 bioactivity at the target site, enhancing immune cell proliferation and infiltration, thereby improving treatment efficacy while reducing systemic toxicity.
Implementation Method 1
a second polypeptide comprising an amino acid sequence, wherein the amino acid sequence is capable of being cleaved by a protease
Data Source
AI summary
Provided herein are chimeric nucleic acid sequences encoding chimeric polypeptides. Also provided herein are chimeric polypeptides. Further provided herein are methods of treating a subject with or at risk of developing a cancer. The methods comprise selecting a subject with or at risk of developing a cancer, and administering to the subject an effective amount of the chimeric polypeptides provided herein.