Fusion Protein of Human Serum Albumin and Interleukin-2 for Extended Half-Life
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Solution Overview
Problem
Current recombinant human interleukin-2 (IL-2) therapies face challenges due to short half-life, severe cytokine storm side effects, and limited clinical efficacy, necessitating the development of a long-acting, safer alternative that can enhance anti-tumor activity when used alone or in combination with anti-PD-1/L1 antibodies.
Innovation Solution
A recombinant fusion protein comprising human serum albumin and mutant human interleukin-2, designed to reduce binding to IL-2 receptor alpha, enhance binding to IL-2 receptor beta/gamma, and extend in vivo half-life, thereby improving tumor inhibition and reducing cytotoxicity, allowing for less frequent administration and increased clinical efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If recombinant human interleukin-2 is used for tumor treatment, then anti-tumor activity is improved, but half-life is too short requiring frequent administration
Solution Approach 1:
The patent combines human serum albumin (HSA) with interleukin-2 (IL-2) to create a fusion protein. The HSA component provides a long half-life (20 days) characteristic, while the IL-2 component retains the anti-tumor activity. This merging of two proteins with complementary properties resolves the contradiction between short half-life and frequent administration requirements.
Solution Approach 2:
The fusion protein represents a composite biological material combining two distinct protein functions. The HSA portion contributes structural stability and extended circulation time, while the IL-2 portion provides immunomodulatory and anti-tumor effects, creating a composite therapeutic agent with optimized pharmacokinetic and pharmacodynamic properties.
2Reliability
If wild-type interleukin-2 is used to enhance immune response, then anti-tumor efficacy is improved, but cytokine storm and severe side effects occur
Solution Approach 1:
The patent applies local quality modification by introducing specific amino acid mutations at particular positions within the IL-2 portion of the fusion protein (e.g., positions 38, 42, 72, 80, 85, 92). These localized changes selectively reduce binding affinity to IL-2Rα (which mediates cytokine storm) while preserving or enhancing binding to IL-2Rβ/γ (which mediates anti-tumor effects), thus improving safety without sacrificing efficacy.
Solution Approach 2:
The patent changes the biochemical parameters of IL-2 by introducing amino acid substitutions that alter receptor binding characteristics. Specifically, mutations such as R38A, F42A, Y45A, L72G, and C125A modify the interaction parameters with different IL-2 receptors, reducing harmful cytokine storm while maintaining therapeutic anti-tumor activity.
3Object-generated harmful factors
If amino acid substitutions are introduced to reduce IL-2Rα binding, then cytokine storm is reduced, but binding to IL-2Rβ/γ must be enhanced to maintain efficacy
Solution Approach 1:
The patent applies local quality modification by introducing specific amino acid mutations at particular positions within the IL-2 portion of the fusion protein (e.g., positions 38, 42, 72, 80, 85, 92). These localized changes selectively reduce binding affinity to IL-2Rα (which mediates cytokine storm) while preserving or enhancing binding to IL-2Rβ/γ (which mediates anti-tumor effects), thus improving safety without sacrificing efficacy.
Solution Approach 2:
The patent changes the biochemical parameters of IL-2 by introducing amino acid substitutions that alter receptor binding characteristics. Specifically, mutations such as R38A, F42A, Y45A, L72G, and C125A modify the interaction parameters with different IL-2 receptors, reducing harmful cytokine storm while maintaining therapeutic anti-tumor activity.
4Duration of action of moving object
If fusion protein is designed to extend half-life, then administration frequency is reduced, but production complexity increases
Solution Approach 1:
The patent combines human serum albumin (HSA) with interleukin-2 (IL-2) to create a fusion protein. The HSA component provides a long half-life (20 days) characteristic, while the IL-2 component retains the anti-tumor activity. This merging of two proteins with complementary properties resolves the contradiction between short half-life and frequent administration requirements.
Data Source
AI summary
Provided is a fusion protein of human serum albumin or a wild type thereof and human interleukin-2 or a mutation thereof, said fusion protein has a significantly extended in vivo half-life relative to recombinant interleukin-2, can be used alone for treating a tumor, and improves anti-tumor efficacy of an anti-PD-1 antibody or an anti PD-L1-antibody.