Masked IL-2 Fc Fusion for Tumor-Selective Cytokine Activation
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Solution Overview
Problem
Cytokines administered for cancer treatment have a short half-life and can cause adverse health outcomes due to systemic immune activation, necessitating frequent dosing and carrier moieties to extend half-life and reduce toxicity.
Innovation Solution
Development of masked cytokines comprising an IL-2 cytokine, a VHH masking moiety, and an engineered Fc domain, where the masking moiety inhibits cytokine function in undesired targets and is released upon cleavage at tumor sites, activating IL-2 polypeptide function selectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If cytokines are administered to patients for cancer treatment, then anti-tumor cytotoxicity is induced, but the cytokines have a very short half-life requiring frequent dosing
Solution Approach 1:
The patent introduces an Fc domain as an intermediary carrier moiety that binds to the cytokine, forming a cytokine-Fc fusion protein. The Fc domain interacts with the neonatal Fc receptor (FcRn) to mediate prolonged circulation and reduce clearance, thereby extending the half-life of the cytokine without requiring frequent dosing.
Solution Approach 2:
The patent creates a composite cytokine-Fc fusion protein that combines the therapeutic cytokine with the Fc domain. This composite structure leverages the properties of both components: the cytokine provides anti-tumor activity while the Fc domain provides extended half-life through FcRn-mediated recycling.
2Reliability
If high doses of cytokine are administered, then anti-tumor efficacy is enhanced, but adverse health outcomes such as vascular leakage occur through systemic immune activation
Solution Approach 1:
The patent modifies the cytokine to have different activity levels in different locations: the cytokine-Fc fusion protein has reduced systemic activity to minimize toxicity but retains full activity at the tumor site where it is needed. This is achieved through the masking moiety that blocks cytokine activity until localized at the tumor.
Solution Approach 2:
The Fc domain serves as an intermediary that allows the cytokine to be delivered to the tumor site while controlling its activation. The Fc domain mediates both the extended circulation and the targeted delivery, reducing systemic exposure and adverse effects.
3Duration of action of moving object
If carrier moieties are fused to cytokine to extend half-life, then duration of action is improved, but device complexity increases due to additional components
Solution Approach 1:
The patent merges the cytokine and Fc domain into a single fusion protein, combining two functional elements (therapeutic activity and half-life extension) into one molecular entity. This reduces the complexity of administering separate components while achieving both goals simultaneously.
4Object-affected harmful factors
If masking moiety is used to inhibit cytokine function in undesired targets, then toxicity is reduced, but manufacturing precision requirements increase
Solution Approach 1:
The masking moiety is pre-attached to the cytokine in the fusion protein, creating a pre-masked state before administration. This preliminary masking prevents systemic toxicity from the outset, and the unmasking occurs automatically upon tumor localization, reducing the need for precise dosing control.
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 cytokines achieve effective masking and targeted activation of IL-2 in tumors, inhibiting cytokine function in undesired targets and enhancing in vivo efficacy with high tumor growth inhibition.
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 interleukin 2 (IL-2) polypeptide, a VHH masking moiety, an anti-PD1 targeting moiety, and an engineered Fc domain comprising a tumor-associated protease cleavage site. In such masked cytokine, the IL-2 polypeptide is engineered to be activatable by a protease at a target site, such as in a tumor microenvironment. 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 cleavage site in the Fc domain, the IL-2 polypeptide becomes activated, which renders it capable of binding to its cognate receptor or protein with increased affinity.