HBV Polymerase Mutant for T-Cell Immunity
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Solution Overview
Problem
Current treatments for chronic hepatitis B virus (HBV) infection are inadequate, with antiviral therapies causing side effects and temporary efficacy due to the persistence of covalently closed circular DNA in hepatocytes, and existing immunotherapies failing to induce effective T-cell responses in chronically infected patients.
Innovation Solution
A mutant polymerase polypeptide with an internal deletion disrupting polymerase activity, specifically targeting the YMDD motif, is used in combination with other HBV polypeptides and standard care to elicit an immune response and treat HBV infection, leveraging vector systems for expression and immunization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antiviral therapies are used to treat chronic HBV infection, then viral replication is inhibited, but side effects occur and efficacy is temporary due to persistence of cccDNA
Solution Approach 1:
The patent uses the persistent cccDNA, which causes chronic infection, as the source of continuous antigen presentation. By expressing mutant polymerase that cannot replicate virus but can present antigens, the harmful persistence is converted into beneficial continuous immune stimulation.
Solution Approach 2:
The mutant polymerase acts as an intermediary between the persistent cccDNA and the immune system. It processes viral antigens for presentation without producing infectious virus, mediating between viral persistence and immune activation.
2Reliability
If existing immunotherapies are used to induce T-cell responses, then immune activation is attempted, but effective T-cell responses are not induced in chronically infected patients
Solution Approach 1:
The patent extracts the polymerase domain from the complete viral polymerase and creates a mutant version that retains antigen presentation capability but loses viral replication function. This simplified construct is more effective than complex immunotherapies.
Solution Approach 2:
The patent changes the functional parameters of the polymerase by introducing mutations (e.g., in the YMDD motif) that abolish enzymatic activity while preserving or enhancing immunogenicity. This parameter change creates a superior immunotherapeutic agent.
3Productivity
If complete HBV polymerase is expressed, then viral replication occurs, but this prevents effective immune response induction
Solution Approach 1:
The patent segments the polymerase function into separate domains: the N-terminal domain for antigen presentation and the C-terminal polymerase domain for replication. By mutating the replication domain while preserving the presentation domain, it achieves immune activation without viral replication.
Solution Approach 2:
Instead of using wild-type polymerase that replicates virus and suppresses immunity, the patent inverts the approach by creating a polymerase mutant that cannot replicate but actively stimulates immune response through antigen presentation.
Data Source
AI summary
The present invention relates to polymerase HBV mutant polypeptides comprising a mutated polymerase domain which is functionally disrupted for polymerase activity and fusion proteins comprising such polymerase mutant polypeptide. The present invention also relates to a nucleic acid molecule and an expression vector for expressing said polymerase mutant polypeptide as well as a composition which can be used for eliciting an immune response to HBV with the goal of providing a protective or therapeutic effect against HBV infection.