Inducible IL-12 Polypeptide Complexes for Targeted Oncology Therapy
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Solution Overview
Problem
Interleukin-12 (IL-12) therapies face challenges due to a narrow therapeutic window, short serum half-life, and systemic toxicities, limiting their clinical effectiveness in oncology due to the need for large doses and inability to effectively target and control cytokine activity.
Innovation Solution
Development of inducible IL-12 polypeptide complexes comprising attenuated IL-12 subunits p35 and p40, a half-life extension element, and a protease cleavable linker, which includes an IL-12 blocking element, allowing for controlled release of active IL-12 with extended half-life and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If large quantities of IL-12 are administered to achieve desired levels at the tumor site, then the therapeutic effect is improved, but systemic toxicities and harmful effects are exacerbated
Solution Approach 1:
The patent segments the IL-12 molecule into two separate polypeptide chains (p35 and p40 subunits) that can be administered separately or as a complex, allowing for controlled assembly at the target site while reducing systemic exposure to high doses of intact IL-12
Solution Approach 2:
The patent uses a blocking element (such as an antibody or antibody fragment) as an intermediary that binds to IL-12 and prevents its systemic activity, while allowing controlled release at the tumor site through protease cleavage, thereby reducing systemic toxicities
2Duration of action of moving object
If high doses of IL-12 are administered to overcome short half-life, then the therapeutic effect is improved, but the narrow therapeutic window is exceeded and toxicities increase
Solution Approach 1:
The patent incorporates a half-life extension element into the IL-12 construct before administration, which pre-extends the circulating half-life of the cytokine, allowing for sustained therapeutic levels without requiring excessive dosing that would exceed the therapeutic window
Solution Approach 2:
The blocking element serves as a mediator that temporarily holds IL-12 in an inactive state during circulation, preventing premature activity and allowing the extended half-life construct to remain stable without causing toxicities, until protease cleavage activates it at the target site
3Reliability
If IL-12 is administered to achieve therapeutic effect, then the immune response is improved, but the ability to effectively target and control cytokine activity is limited
Solution Approach 1:
The patent creates a dynamic IL-12 system where the blocking element can be cleaved by proteases at the tumor site, converting the construct from an inactive state to an active state in response to local conditions, thereby enabling targeted and controlled cytokine activity
Solution Approach 2:
The blocking element acts as a controllable intermediary that can be removed or activated by protease cleavage, providing a mechanism to control IL-12 activity spatially and temporally, ensuring therapeutic effect is achieved only at the intended site of action
Data Source
AI summary
Provided herein are IL-12 polypeptide complexes and/or IL23 polypeptide complexes comprising IL-12 or IL-23, a half-life extension element, an IL-12 or IL-23 blocking element and a protease cleavable linker. Also provided herein are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors, host cells for making such polypeptide complexes. Also disclosed are methods of using the polypeptide complexes in the treatment of diseases, conditions and disorders.