Antibody-Drug Conjugates Targeting EGFR in Ovarian Cancer
Sheila Almaraz
Centro de Investigación del Cáncer (Universidad de Salamanca - CSIC)
Ovarian cancer is a highly lethal and heterogeneous malignancy, often diagnosed at advanced stages, with limited treatment options once the disease progresses beyond the standard of
care. Targeted therapies, including monoclonal antibodies and antibody-drug conjugates (ADCs), offer a promising approach by enhancing specificity and minimizing systemic toxicity.
In this study, we evaluated the efficacy of a novel ADC composed of Cetuximab (an anti-EGFR humanized antibody) conjugated to monomethyl auristatin F (MMAF). In vitro assays using
seven ovarian cancer cell lines revealed that Cetuximab-vc-MMAF induced potent anti-proliferative effects, with ≥80% inhibition at low picomolar concentrations. Mechanistic studies confirmed activation of DNA damage and apoptosis pathways, alongside with mitotic arrest and EGFR-dependent internalization. Based on these results, in vivo experiments were performed using two xenograft models in nude mice. The ADC significantly inhibited tumor growth, achieving complete regression in some cases, with no signs of systemic toxicity or weight loss. Pharmacokinetic analyses showed efficient tumor accumulation and minimal distribution to non-target tissues. Immunohistochemistry and biochemical assays corroborated the selective localization of the ADC in tumors and the induction of cell death mechanisms consistent with in vitro observations. Overall, these findings demonstrate that Cetuximab-MMAF is a highly potent and selective therapeutic candidate for EGFR-positive ovarian cancer,
with a favorable safety and pharmacological profile, supporting further preclinical development.