pH-Dependent Anti-HBsAg Antibody for Extended HBV Suppression
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Solution Overview
Problem
Current treatments for chronic hepatitis B virus (HBV) infection, including interferons and nucleoside analogs, fail to completely eliminate the virus, and passive immunotherapy with hepatitis B immunoglobulin (HBIG) lacks efficacy and has limitations such as scarce sources, high cost, and potential safety issues.
Innovation Solution
Development of an anti-HBsAg antibody with pH-dependent antigen binding affinity, exhibiting higher binding at neutral pH than acidic pH, and engineered to extend half-life and enhance HBV clearance by modifying the Fc region for enhanced affinity to hFcRn or mFcγRII.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatment drugs (interferons and nucleoside analogs) are used for chronic HBV infection, then viral replication is suppressed, but the HBV virus cannot be completely eliminated and treatment duration is prolonged
Solution Approach 1:
The patent introduces an anti-HBsAg antibody as an intermediary substance that mediates the immune system's ability to recognize and clear HBV-infected cells and viral particles. This antibody acts as a bridge between the host immune system and the virus, enabling more effective viral clearance without requiring prolonged treatment with conventional drugs
2Reliability
If hepatitis B immunoglobulin (HBIG) is used for passive immunotherapy, then antibody-mediated virus neutralization is achieved, but sources are scarce, cost is high, and safety issues arise
Solution Approach 1:
The patent employs a recombinant anti-HBsAg antibody that can be produced through cell culture and purification processes, replacing the need for scarce plasma donations. This engineered antibody provides a stable, scalable, and cost-effective alternative to HBIG while maintaining therapeutic efficacy
Solution Approach 2:
The patent modifies the antibody's Fc region to alter its binding affinity to hFcRn, thereby changing the antibody's pharmacokinetic properties including half-life extension. This parameter change enables the antibody to maintain therapeutic levels in the body for longer periods, reducing dosing frequency and improving manufacturing efficiency
3Quantity of substance
If HBIG is administered to HBV-infected patients, then passive immunotherapy is provided, but obvious therapeutic effect is not achieved
Solution Approach 1:
The patent introduces mutations in the Fc region of the antibody (such as N297A, N434A, N434S mutations) that locally modify the antibody's interaction with hFcRn. This local quality change enhances the antibody's half-life and persistence in the body, allowing it to maintain effective concentrations for longer periods and achieve therapeutic effects that HBIG cannot provide
4Reliability
If conventional treatments are used for chronic HBV infection, then viral replication is inhibited, but HBsAg clearance is insufficient and immune response activation is limited
Solution Approach 1:
The patent utilizes the antibody's ability to bind to HBsAg and form immune complexes, which then engage Fc receptors on immune cells to trigger phagocytosis and complement activation. This feedback mechanism amplifies the immune response, leading to enhanced HBsAg clearance and potential functional cure of chronic HBV infection
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 antibody significantly reduces HBV DNA and HBsAg serum levels, extends antigen suppression time, and reduces treatment frequency, offering a more effective and clinically valuable solution for HBV infection.
Implementation Method 1
The anti-HBsAg antibody of the present invention has a higher binding affinity for HBsAg at neutral pH than at acidic pH
Implementation Method 2
engineered to extend half-life and enhance HBV clearance by modifying the Fc region for enhanced affinity to hFcRn or mFcγRII
Implementation Method 3
a therapeutic effect can be achieved by the antibody-mediated virus neutralization to block HBV from infecting newborn hepatocytes
Implementation Method 4
by the antibody-mediated immune clearance to remove viruses and infected liver cells from the body
Data Source
AI summary
Disclosed are antibodies to anti-hepatitis B surface antigen (HBsAg) (especially humanized antibodies), nucleic acid molecules encoding same, methods for preparing same, and pharmaceutical compositions containing same. The antibodies have higher affinity for HBsAg at neutral pH than at acidic pH, thereby significantly enhancing the virus clearance efficiency and prolonging the virus inhibition time. The antibodies and the pharmaceutical compositions can be used for preventing and/or treating HBV infections or diseases related to HBV infections (e.g., hepatitis B), for neutralizing the virulence of HBV in a subject (e.g., a human), for reducing the serum level of HBV DNA and/or HBsAg in the body of the subject, or for activating the humoral immune response of the subject (e.g., a chronic HBV infected or chronic hepatitis B patient) against HBV.