Conditionally Active Anti-EpCAM Antibodies for pH-Selective Tumor Binding
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Solution Overview
Problem
Existing anti-EpCAM antibodies used in cancer therapy often cause significant side effects due to their affinity for EpCAM expressed on normal epithelial cells, limiting their therapeutic window and efficacy.
Innovation Solution
Development of anti-EpCAM antibodies or antibody fragments with enhanced binding affinity to tumor-specific microenvironments, reducing side effects by minimizing binding to normal tissues, and potentially allowing higher dosages for targeted cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-EpCAM antibodies are used to target cancer cells, then cancer treatment efficacy is improved, but side effects increase due to binding to normal epithelial cells
Solution Approach 1:
The antibody is engineered to have different binding properties in different microenvironments. Specifically, the antibody exhibits high binding affinity to EpCAM in the acidic tumor microenvironment (pH 6.5-7.0) while having reduced binding affinity in normal physiological conditions (pH 7.4-7.8). This local differentiation of binding quality allows selective targeting of cancer cells while sparing normal tissues.
Solution Approach 2:
The invention utilizes pH as a distinguishing parameter between tumor and normal microenvironments. By designing the antibody binding site to be sensitive to pH changes, the antibody's binding affinity is modulated based on the local pH condition. The acidic environment of tumors (pH 6.5-7.0) enhances binding, while neutral pH in normal tissues (pH 7.4-7.8) reduces binding, thereby achieving selective targeting.
2Reliability
If higher dosage of anti-EpCAM antibodies is administered to improve treatment efficacy, then cancer cell targeting is enhanced, but side effects are amplified
Solution Approach 1:
The antibody's binding affinity is made dependent on pH parameter changes. In the acidic tumor microenvironment (pH 6.5-7.0), the antibody maintains high binding affinity even at higher dosages. In normal tissues with neutral pH (pH 7.4-7.8), the binding affinity remains low regardless of dosage increase. This parameter-dependent binding decouples the relationship between dosage and side effects.
3Measurement precision
If conventional anti-EpCAM antibodies are used, then EpCAM expression on tumor cells is targeted, but binding to normal epithelial cells causes toxicity
Solution Approach 1:
The antibody is designed with localized binding quality that differs between tumor and normal microenvironments. The binding site characteristics are optimized to interact strongly with EpCAM in the acidic tumor microenvironment while showing reduced interaction with EpCAM in normal physiological conditions, achieving spatially selective targeting.
Solution Approach 2:
The invention introduces pH as a discriminating parameter for selective binding. The antibody's binding affinity is modulated by pH changes, creating a parameter-based distinction between tumor (acidic, pH 6.5-7.0) and normal (neutral, pH 7.4-7.8) tissues. This allows precise targeting of tumor cells while minimizing binding to normal epithelial cells.
Data Source
AI summary
Isolated polypeptides having a heavy chain variable region and/or light chain variable region that specifically binds to EpCAM protein as well as antibodies and antibody fragments containing the heavy chain variable region and/or the light chain variable region that bind to EpCAM protein. Pharmaceutical compositions and kits comprising the polypeptide and antibodies and antibody fragments containing the polypeptide are also provided.