Activatable IL-2 Proteins with Cleavable Moieties for Tumor-Specific Activation
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Solution Overview
Problem
Current therapeutic proteins, such as IL-2, face challenges in minimizing systemic and off-target side effects due to their broad activity, which can lead to undesirable effects in subjects administered with them, particularly in cancer immunotherapies.
Innovation Solution
Development of activatable proteins, like IL-2 polypeptides, with a cleavable moiety attached that reduces their activity until cleaved by specific proteases upregulated in tumor microenvironments, allowing targeted activation at tumor sites while sparing other tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic proteins like IL-2 are administered systemically, then broad therapeutic activity is achieved, but systemic and off-target side effects increase
Solution Approach 1:
The protein is divided into two functional parts: a stable scaffold that provides structural integrity and a removable activity-modulating moiety (such as a peptide or chemical group) that controls binding activity. This segmentation allows the protein to be administered in an inactive or reduced-activity state and then activated locally through removal of the modulating moiety by proteolytic cleavage or chemical reaction, thereby achieving therapeutic efficacy at the target site while minimizing systemic side effects
Solution Approach 2:
The activity-modulating moiety is attached to the protein scaffold in advance during manufacturing or formulation, creating a pre-configured activatable protein that remains in a reduced-activity state during storage and administration. This preliminary action ensures the protein is delivered systemically in a safe, low-activity form and only becomes fully active after reaching the target tissue and undergoing the activation trigger event
2Adaptability or versatility
If the cleavable moiety is attached to fine-tune protein activity, then binding affinity is reduced, but therapeutic selectivity is improved
Solution Approach 1:
The activity-modulating moiety is strategically attached to specific locations on the protein scaffold where it can locally influence binding interactions with receptors or other proteins. By positioning the modulating group at key interface regions, the invention achieves fine-tuned control over binding affinity and selectivity, allowing the protein to maintain sufficient activity at the target site while reducing off-target binding to non-specific receptors
3Productivity
If IL-2 binds to IL-2 receptor alpha subunit, then broad immune cell activation occurs, but regulatory T cell activation increases causing side effects
Solution Approach 1:
The invention modifies the IL-2 protein by attaching an activity-modulating moiety that changes the protein's binding parameters, specifically reducing its affinity for the IL-2 receptor alpha subunit (CD25) while preserving or enhancing binding to beta and gamma subunits. This parameter change shifts the activation profile away from regulatory T cells (which highly express CD25) toward other immune cell types, thereby maintaining immune activation productivity while reducing harmful side effects from Treg activation
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
This approach enhances the therapeutic efficacy of proteins by selectively activating immune cells at tumor sites, minimizing systemic side effects and improving the safety profile of cancer treatments.
Implementation Method 1
the cleavable moiety can take advantage of increased protease activity, lowered pH, or the reducing environment of a tumor microenvironment to selectively activate a therapeutic protein at the tumor site
Implementation Method 2
the cleavable moiety can take advantage of increased protease activity, lowered pH, or the reducing environment of a tumor microenvironment to selectively activate a therapeutic protein at the tumor site
Data Source
AI summary
The present disclosure relates to activatable proteins which comprise cleavable moieties attached thereto which display an altered activity upon cleavage of the cleavable moieties. The present disclosure also relates to activatable IL-2 polypeptides which comprise cleavable moieties, as well as compositions and methods of use thereof. The present disclosure further relates to cleavable peptides which can be cleaved by multiple proteases, as well as to polypeptides incorporating said cleavable peptides.