Activatable Cytokine Constructs Protease Cleavage Tumor Targeting
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Solution Overview
Problem
Current cytokine therapies, such as those using interleukin-15 (IL-15) and interferons, face challenges due to systemic toxicities and short half-life, leading to limited dosages and side effects, necessitating improved specificity and selectivity to reduce systemic toxicities and enhance therapeutic utility.
Innovation Solution
Development of activatable cytokine constructs (ACCs) comprising monomers with mature cytokine proteins, cleavable moieties, and dimerization domains, where the cleavable moieties act as substrates for proteases overexpressed in diseased tissues, allowing activation only in tumor microenvironments and reducing activity in healthy tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant IL-15 is administered systemically, then antitumor response is enhanced, but systemic toxicity increases and half-life decreases
Solution Approach 1:
The cytokine is divided into separate monomeric units that can only form active dimers when brought together by protease cleavage in the tumor microenvironment, separating the inactive formulation from the active therapeutic effect
Solution Approach 2:
Proteases overexpressed in the tumor microenvironment serve as intermediaries that trigger the activation of the cytokine construct, enabling selective activation at the target site without systemic exposure
2Productivity
If higher dosages of cytokine are administered, then therapeutic effect is improved, but systemic side effects increase
Solution Approach 1:
The cytokine construct is designed to exhibit different properties in different locations: inactive and stable during systemic circulation, but activated and potent when cleaved by tumor-associated proteases at the target site
Solution Approach 2:
The cytokine is pre-formulated in an inactive monomeric state that can be safely administered systemically, and is activated only when it reaches the tumor microenvironment where proteases are present
3Reliability
If cytokine activity is increased, then antitumor response is enhanced, but half-life in vivo decreases
Solution Approach 1:
The cytokine construct transitions from a stable inactive monomeric state during circulation to an active dimeric state upon protease cleavage, dynamically adapting its activity and stability based on the local environment
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
ACCs achieve reduced toxicity, enable higher effective dosages, and increase the therapeutic window by selectively activating in diseased tissues, thereby minimizing systemic side effects and improving targeting to cancerous tissues.
Implementation Method 1
the cleavable moieties function as substrates for a protease
Data Source
AI summary
Provided herein are activatable cytokine constructs that include: (a) a first monomer construct comprising a first mature cytokine protein (CP1), a first cleavable moiety (CM1), and a first dimerization domain (DD1), wherein the CM1 is positioned between the CPI and the DD1; and (b) a second monomer construct comprising a second mature cytokine protein (CP2), a second cleavable moiety (CM2), and a second dimerization domain (DD2), where the CM2 is positioned between the CP2 and the DD2, where: the CM1 and the CM2 function as a substrate for a protease; the DD1 and the DD2 bind each other, and where the ACC is characterized by a reduction in at least one activity of the CP1 and/or CP2 as compared to a control level of the at least one activity of the CP1 and/or CP2.