Bispecific HBsAg-CD3 Antibodies for Safer T-Cell Redirection
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Solution Overview
Problem
Current treatments for Hepatitis B virus (HBV) infection, such as antiviral drugs, fail to eliminate covalently closed circular DNA (cccDNA) from hepatocytes, leading to potential recurrence of infection, and existing CD3 antibodies suffer from adverse reactions and poor druggability.
Innovation Solution
Development of a bispecific antibody in the form of IgG and scFv or VHH nanoantibody that specifically binds to HBsAg and CD3, with reduced affinity for CD3, allowing for targeted T-cell redirection to HBV-infected cells, enhancing viral elimination and reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high-affinity CD3 antibodies are used to redirect T cells to HBV-infected cells, then T cell redirection efficiency is improved, but adverse reactions and cytotoxicity increase
Solution Approach 1:
The patent modifies the affinity parameter of the CD3 antibody binding domain by introducing specific mutations (e.g., in the CDR regions) to reduce its binding strength to CD3. This parameter change allows the bispecific antibody to redirect T cells to HBV-infected cells with sufficient efficiency while reducing excessive T cell activation and associated adverse reactions such as cytokine release syndrome and hepatocyte cytotoxicity.
2Reliability
If antiviral drugs are used to suppress viral replication, then viral replication is controlled, but HBV cccDNA cannot be eliminated leading to potential recurrence
Solution Approach 1:
The patent introduces a bispecific antibody as an intermediary therapeutic agent that bridges T cells and HBV-infected cells. This antibody mediates immune-mediated elimination of infected cells carrying persistent cccDNA, complementing antiviral drugs that control viral replication. The combination approach addresses both viral suppression and clearance of reservoir cells, reducing recurrence risk.
3Reliability
If existing CD3 antibodies are used for T cell redirection, then T cell activation is achieved, but druggability and safety profile deteriorate
Solution Approach 1:
The patent creates a composite molecular structure consisting of a bispecific antibody that combines a modified CD3 binding domain with an HBV surface antigen binding domain. This composite structure integrates the beneficial T cell activation capability of anti-CD3 antibodies with the target specificity of anti-HBsAg antibodies, while the modified CD3 domain reduces adverse effects, improving overall druggability and safety profile.
Data Source
AI summary
Provided are bispecific antibodies that may specifically target both HBV surface antigen (HBsAg) and CD3 protein and pharmaceutical compositions comprising the same. Particularly, provided are nucleic acid molecules encoding the bispecific antibodies or fragments thereof and vectors including the nucleic acid molecules. Also provided uses of the bispecific antibodies or fragments thereof and the nucleic acid molecules and the vectors in preparation of medicines for preventing or treating HBV infection and other related diseases.