Fc-Interleukin Heterodimers for Stable Antitumor Immunity
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Solution Overview
Problem
Current immunoregulators like interleukins have a short serum half-life, leading to instability and reduced efficacy in treating cancer and tumors due to factors such as renal clearance and proteolytic degradation, necessitating the development of long-acting, high-yield alternatives with minimal impurities.
Innovation Solution
The development of proteinaceous heterodimers comprising Fc subunits with fused interleukins, specifically IL10, that form stable complexes to enhance antitumor immunity, with modifications promoting heterodimerization and reducing homodimer formation, thereby increasing stability and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If interleukins are used as immunoregulators, then antitumor immunity can be activated, but serum half-life is short leading to reduced efficacy
Solution Approach 1:
The patent combines interleukin-10 with Fc subunits to create fusion proteins that form heterodimers. The Fc portion provides long circulation half-life while the interleukin-10 portion maintains immunoregulatory activity, thus merging the advantages of both components to resolve the contradiction between maintaining antitumor immunity and extending serum half-life.
Solution Approach 2:
The invention creates composite protein structures by fusing interleukin-10 with Fc subunits. This composite structure combines the immunomodulatory properties of interleukin-10 with the extended half-life characteristics of Fc-containing proteins, thereby achieving both reliable antitumor immunity and prolonged duration of action.
2Reliability
If immunoregulatory molecules are introduced into tumor cells, then immunogenicity can be enhanced, but expression and stability are far from satisfactory
Solution Approach 1:
The patent merges interleukin-10 with Fc subunits to create fusion proteins that form stable heterodimers. The Fc portion provides structural stability and extends circulation half-life, while the interleukin-10 portion enhances immunogenicity, thus resolving the contradiction between enhancing immunogenicity and maintaining stability.
3Productivity
If high yield production is pursued, then industrial-scale production becomes feasible, but purification complexity increases due to impurities
Solution Approach 1:
The patent introduces asymmetric amino acid substitutions at the Fc-Fc interface (knob-in-hole mutations) that promote heterodimer formation while preventing homodimer formation. This asymmetric design ensures that the heterodimer is the predominant species produced, greatly simplifying purification processes and reducing impurity removal requirements while maintaining high yield production.
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 proteinaceous heterodimers provide sustained antitumor activity with reduced impurities, effectively inhibiting tumor growth and offering a high-yield, long-acting solution for cancer treatment by stabilizing interleukin activity and enhancing immune response.
Implementation Method 1
the first monomeric member associates with the second monomeric member to form the heterodimer through complexation of the first Fc subunit with the second Fc subunit
Data Source
AI summary
Provided are proteinaceous heterodimers, pharmaceutical compositions, medicaments and/or kits comprising the proteinaceous heterodimers, methods for producing the proteinaceous heterodimers, and uses thereof.