DATOPOTAMAB DERUXTECAN: A BREAKTHROUGH ANTIBODY-DRUG CONJUGATE TRANSFORMING TRIPLE-NEGATIVE BREAST CANCER THERAPY

Sugapriyan G., Prasanth J., Subhiksha Sri K., Sundar Raj P.*, Sambath Kumar R.

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for 15–20% of breast cancers and is associated with poor prognosis due to the lack of estrogen, progesterone, and HER2 receptors, limiting targeted treatment options. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC) developed to address this unmet need by targeting trophoblast cell surface antigen 2 (TROP2), which is highly expressed in TNBC. It comprises a humanized anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload, deruxtecan, via a cleavable linker. Upon binding to TROP2 on cancer cells, the drug is internalized and releases its cytotoxic payload, causing DNA damage and apoptosis, while also producing a bystander effect that enhances tumor cell killing in heterogeneous tumors. Preclinical and clinical studies have demonstrated significant antitumor activity, with objective response rates of approximately 30–40% in heavily pretreated patients and durable clinical benefits. Clinical trials under the TROPION program further highlight its efficacy and manageable safety profile, with common adverse effects including stomatitis, nausea, and fatigue. Ongoing research is exploring its role in combination therapies and earlier stages of disease. Overall, Dato-DXd represents a promising advancement in precision oncology, offering a targeted and effective therapeutic strategy that has the potential to improve outcomes in patients with TNBC.Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for 15–20% of breast cancers and is associated with poor prognosis due to the lack of estrogen, progesterone, and HER2 receptors, limiting targeted treatment options. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC) developed to address this unmet need by targeting trophoblast cell surface antigen 2 (TROP2), which is highly expressed in TNBC. It comprises a humanized anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload, deruxtecan, via a cleavable linker. Upon binding to TROP2 on cancer cells, the drug is internalized and releases its cytotoxic payload, causing DNA damage and apoptosis, while also producing a bystander effect that enhances tumor cell killing in heterogeneous tumors. Preclinical and clinical studies have demonstrated significant antitumor activity, with objective response rates of approximately 30–40% in heavily pretreated patients and durable clinical benefits. Clinical trials under the TROPION program further highlight its efficacy and manageable safety profile, with common adverse effects including stomatitis, nausea, and fatigue. Ongoing research is exploring its role in combination therapies and earlier stages of disease. Overall, Dato-DXd represents a promising advancement in precision oncology, offering a targeted and effective therapeutic strategy that has the potential to improve outcomes in patients with TNBC.

Keywords: Datopotamab deruxtecan (Dato-DXd), Antibody-drug conjugate (ADC), TROP2 targeting, Topoisomerase I inhibitor, Precision oncology, Tumor heterogeneity, Triple Negative Breast Cancer, Monoclonal antibody, Cytotoxic payload, DNA damage.