SNAP-Tag-Based Antibody–Drug Conjugates Targeting Epidermal Growth Factor Receptor 1, Epidermal Growth Factor Receptor 2, Trophoblast Cell-Surface Antigen 2, and Tissue Factor for Ovarian Cancer Treatment

TL;DR

Researchers developed new antibody-drug conjugates targeting specific proteins on ovarian cancer cells, showing promising results in killing cancer cells.

Contribution

Four novel ADCs using SNAP-tag technology for site-specific conjugation were developed and tested for ovarian cancer treatment.

Findings

All four ADCs showed specific binding and internalization in ovarian cancer cells.

The ADCs induced apoptosis at nanomolar concentrations in four ovarian cancer cell lines.

Preliminary results suggest potent and specific cytotoxicity in a dose-dependent manner.

Abstract

The ovarian cancer is a heterogeneous and most malignant
form of
gynecologic cancer. Despite surgical intervention and systemic chemotherapy,
treatment options for this cancer remain limited. Antibody–drug
conjugate (ADC) represents a novel targeted therapy that uses an antibody
to specifically deliver toxins to tumor sites. With the approval of
the first ADC targeting ovarian cancer, more ADCs are currently under
preclinical investigation or clinical trials to expand therapeutic
options. In this study, we developed four ADCs targeting epidermal
growth factor receptor (EGFR), epidermal growth factor receptor 2
(Her2), trophoblast cell-surface antigen 2 (Trop2), and tissue factor
(TF) that are highly expressed on ovarian cancer cells. Our ADCs are
constructed using single chain antibody fragments (scFvs) as the antibody
backbone, with the cytotoxic agent monomethyl auristatin E conjugated
via SNAP-tag technology, offering a high site-specific conjugation
efficiency. All four ADCs preliminarily demonstrated specific binding
and internalization, as verified by flow cytometry and fluorescence
microscopy. Additionally, the ADCs exhibited potent and specific cytotoxicity
in a dose-dependent manner in four ovarian cancer cell lines, inducing
apoptosis at nanomolar concentrations. These constructs showed encouraging
preliminary characteristics, although further studies are required
to validate their therapeutic potential.

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