Fusion Polypeptides for Hepatitis Treatment
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Solution Overview
Problem
Current treatments for hepatitis C and hepatitis B, involving PEGylated interferon alpha, are associated with significant toxicities and poor patient compliance due to flu-like symptoms, neuropsychiatric issues, and hematological disorders, necessitating the development of better-tolerated and more effective antiviral therapies.
Innovation Solution
Development of modified human interleukin 28B (IL28B) and human interleukin 29 (IL29) fusion polypeptides, produced in prokaryotic systems like E. coli, which are used to treat viral infections, autoimmune diseases, and cancers, with a focus on minimizing immunogenicity and enhancing chemistry stability through specific amino acid modifications and PEGylation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PEGylated interferon alpha is used to treat hepatitis C and hepatitis B, then antiviral activity is achieved, but significant toxicities occur including flu-like symptoms, neuropsychiatric issues, and hematological disorders
Solution Approach 1:
The invention segments the interferon molecule by creating fusion polypeptides that combine only the Fc region of interferon alpha with the cytokine domain of IL-28B or IL-29, separating the antiviral function from the toxic components. This segmentation allows retention of antiviral activity while eliminating flu-like symptoms and hematological disorders associated with full-length interferon alpha
Solution Approach 2:
The invention extracts and removes the toxic portions of interferon alpha (the cytokine domain) while retaining only the Fc region for fusion with IL-28B or IL-29. This extraction eliminates the harmful factors including neuropsychiatric issues and hematological disorders while preserving antiviral efficacy through the retained Fc region
2Reliability
If PEGylated interferon alpha is used to treat viral infections, then antiviral effects are achieved, but patient compliance deteriorates due to poor tolerability
Solution Approach 1:
By segmenting interferon alpha into only its Fc region for fusion with IL-28B or IL-29, the invention creates a molecule that retains antiviral activity but lacks the toxic cytokine domain. This segmentation improves patient tolerability and compliance while maintaining antiviral efficacy
Solution Approach 2:
The invention changes the molecular parameters by creating fusion polypeptides with modified amino acid sequences (e.g., E22G, N26G, S88G mutations) and PEGylation, which alter the pharmacokinetic and pharmacodynamic properties to improve tolerability and half-life, thereby enhancing patient compliance
3Productivity
If fusion polypeptides are produced in prokaryotic systems like E. coli, then production efficiency is improved, but protein folding and post-translational modifications may be limited
Solution Approach 1:
The invention optimizes production parameters by engineering specific amino acid mutations (E22G, N26G, S88G) that enhance solubility and folding in prokaryotic systems. These parameter changes enable efficient production in E. coli while maintaining proper protein structure and function
Data Source
AI summary
Disclosed are fusion polypeptides comprising fragments from a first and a second isoform of an interferon lambda family, nucleic acids encoding the fusion polypeptides, and vectors and host cells containing the same, and methods of making and using such compositions in treatment of interferon lambda-related diseases, disorders, and conditions.