Masked IL-2 Cytokine With VHH Protease Cleavage
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Solution Overview
Problem
Current cytokine therapies for cancer, such as Proleukin (aldesleukin), have a short half-life and require frequent dosing, leading to adverse health outcomes due to systemic immune activation, highlighting the need for IL-2 polypeptide therapeutics that effectively target tumors without systemic side effects.
Innovation Solution
A masked cytokine comprising an attenuated IL-2 polypeptide and a VHH masking moiety, where the VHH binds to IL-2, inhibiting its activity in undesired targets and is released upon cleavage in tumor cells, activating IL-2 function selectively in tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokine therapy is administered to stimulate immune system, then anti-tumor cytotoxicity is induced, but systemic immune activation causes adverse health outcomes
Solution Approach 1:
The patent applies local quality by creating a masked IL-2 cytokine where the masking moiety is selectively removed in the tumor microenvironment through proteolytic cleavage. This ensures IL-2 activity is localized to tumor sites rather than distributed systemically, achieving anti-tumor cytotoxicity without widespread immune activation. The tumor-specific proteases present in the tumor microenvironment selectively cleave the masking moiety, activating IL-2 only where needed.
Solution Approach 2:
The masking moiety serves as an intermediary that temporarily inhibits IL-2 activity in circulation and non-target tissues. This intermediary component allows the cytokine to reach the tumor site without causing systemic effects, and is subsequently removed by tumor-specific proteases to activate IL-2 function only at the target site.
2Reliability
If high doses of cytokine are administered to treat cancer, then tumor growth inhibition is achieved, but vascular leakage and adverse outcomes occur
Solution Approach 1:
The masked IL-2 cytokine ensures high local concentration of active IL-2 at the tumor site through selective proteolytic cleavage of the masking moiety by tumor-specific proteases. This localized activation achieves potent tumor growth inhibition without requiring systemically high doses that would cause vascular leakage and other adverse effects.
3Reliability
If recombinant IL-2 is used to treat cancer, then immune activation is achieved, but short half-life requires frequent dosing
Solution Approach 1:
The masking moiety is attached to the IL-2 cytokine in advance, creating a pro-drug-like structure that remains stable in circulation. This preliminary masking extends the effective half-life by preventing premature degradation or clearance, while the tumor-specific proteolytic cleavage is triggered only at the target site to release active IL-2.
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 masked cytokine achieves effective masking in non-target environments, efficient activation in tumors, and high tumor growth inhibition, with enhanced safety profiles by minimizing systemic immune activation.
Implementation Method 1
A VHH masking moiety binds to the IL-2 cytokine and inhibits a biological activity of the cytokine in undesired targets
Implementation Method 2
Upon cleavage in desired targets (e.g., tumor), the masking moiety is released from the cytokine, activating the function of the IL-2 polypeptide
Data Source
AI summary
The present invention provides, among other things, a masked cytokine comprising an attenuated interleukin 2 (IL-2) polypeptide, a VHH masking moiety, a carrier moiety and anti-PD1 targeting moiety. In some embodiments, the IL-2 polypeptide is engineered to be activatable by a protease at a target site, such as in a tumor microenvironment, by including a proteolytically cleavable linker. The VHH masking moiety blocks, occludes, inhibits (e.g., decreases) or otherwise prevents (e g masks) the activity or binding of the cytokine to its cognate receptor or protein. Upon proteolytic cleavage of the cleavable linker at the target site, the IL-2 polypeptide becomes activated, which renders it capable of binding to its cognate receptor or protein with increased affinity.