Potent anti-tumor activity of CD98hc-targeted antibody-drug conjugates in ovarian cancer

Ovarian cancer remains a challenging malignancy with high recurrence rates and limited long-term therapeutic success. Antibody–drug conjugates (ADCs) represent a promising therapeutic class capable of delivering potent cytotoxic agents selectively to tumor cells. In this study, we investigated the potential of CD98hc, a transmembrane glycoprotein involved in amino acid transport and cell signaling, as a novel target for ADCs in ovarian cancer. Western blotting and immunohistochemistry analyses revealed higher CD98hc expression in ovarian tumor tissues compared to normal ovarian tissue. Flow cytometry and immunofluorescence studies confirmed that an antibody against the extracellular domain of CD98hc bound cell surface CD98hc and internalized to lysosomes. Using this antibody, we generated ADCs containing the payloads DM1, MMAF, or DXd. Among these, the anti-CD98hc-MMAF construct showed superior cytotoxicity in ovarian cancer cell lines, with IC 50 values in the picomolar range. The anti-CD98hc-MMAF ADC also effectively inhibited the proliferation of tumor cells cultured from ascitic fluids of ovarian cancer patients. Mechanistic studies showed that anti-CD98hc-MMAF induced G2/M cell cycle arrest, mitotic spindle disruption, and apoptotic cell death. In vivo, treatment with a humanized anti-CD98hc-MMAF ADC significantly suppressed tumor growth and metastatic implantation in xenografted mice, without apparent toxicity. These findings validate CD98hc as a promising target for ADC therapy in ovarian cancer and support the clinical development of anti-CD98hc-MMAF.