Engineered TCR Binding Molecules for HBV-Infected Cell Clearance
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Solution Overview
Problem
Current treatments for chronic hepatitis B virus (HBV) infection, such as antiviral drugs, fail to eliminate the virus and are associated with resistance and toxicity, while T cell responses in chronic infections are impaired, necessitating new therapies to restore viral clearance.
Innovation Solution
Development of specific binding molecules, including T cell receptor (TCR) variable domains, that bind to the GLSPTVWLSV peptide-HLA-A*02 complex with engineered mutations for enhanced affinity and specificity, capable of redirecting and activating non-exhausted T cells to clear HBV-infected cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antivirals are used to suppress viral replication, then progression of liver damage is slowed, but the virus is not eliminated and long-term use leads to resistance and toxicity
Solution Approach 1:
The patent replaces the mechanical/chemical suppression approach of antivirals with a biological immune-mediated approach. Engineered TCRs are designed to specifically recognize HBV envelope protein peptides presented by HLA molecules, enabling the patient's own T cells to identify and eliminate infected cells through natural immune mechanisms rather than pharmacological suppression.
Solution Approach 2:
The invention enables the patient's immune system to serve itself by restoring T cell function against HBV. The engineered TCRs are introduced into the patient's T cells, allowing them to autonomously recognize and kill infected cells without requiring continuous external antiviral medication, thereby eliminating the need for long-term drug therapy and its associated toxicity and resistance issues.
2Productivity
If T cell response is strengthened to clear HBV, then functional cure may be achieved, but the immune response is currently exhausted and impaired in chronic infection
Solution Approach 1:
The patent applies parameter changes by engineering the TCRs with optimized complementarity determining regions (CDRs) to enhance their binding affinity and specificity for the HBV peptide-HLA complex. This modifies the functional parameters of T cell recognition, enabling exhausted T cells to regain their ability to effectively identify and respond to infected cells despite the chronic infection environment.
Solution Approach 2:
The invention creates optimized copies of TCRs with improved binding properties. By designing and introducing engineered TCR variants with enhanced affinity for the GLSPTVWLSV peptide-HLA-A*02:01 complex, the patent provides T cells with superior recognition capabilities compared to their native, exhausted state, thereby restoring productive antiviral immunity.
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 specific binding molecules demonstrate high affinity and specificity for HBV-infected cells, facilitating viral clearance and potentially offering a functional cure by restoring T cell-mediated responses.
Implementation Method 1
TCRs are designed to recognize short peptide antigens that are displayed on the surface of antigen presenting cells in complex with Major Histocompatibility Complex (MHC) molecules
Data Source
AI summary
The present invention relates to specific binding molecules that bind the HLA-A*02 restricted peptide GLSPTVWLSV (SEQ ID NO: 1) derived from HBV envelope protein. The specific binding molecules may comprise alpha and/or beta TCR variable domains and may comprise non-natural mutations within the alpha and/or beta variable domains relative to a native TCR. The specific binding molecules of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of infectious or malignant disease.