Exploiting the highly targeted nature of
monoclonal antibodies to deliver selectively to
tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future.
Antibody-drug conjugates may currently hold an unprecedented potential; however, there are multiple unique challenges in their development, and the recent successes have come hand in hand with significant technologic advances in their chemistry and manufacturing. Over the years, multiple factors have been identified to affect the pharmacokinetic and pharmacodynamic properties of an
antibody-drug conjugate, but many important details remain to be further investigated. These factors pertain to the target
antigen, antibody, conjugate, linker, as well as the nature of the
malignancy under treatment.
Glembatumumab vedotin is an
antibody-drug conjugate targeting
glycoprotein non-metastatic B (GPNMB) expressed in multiple
malignancies, including
breast cancer. The expression of this
protein has been associated with an aggressive malignant phenotype, invasive growth, angiogenesis, and generation of skeletal
metastases.
Glembatumumab vedotin is currently in early stages of clinical development in
melanoma and
breast cancer. Although in unselected patients with metastatic
breast cancer glembatumumab vedotin was not superior to other agents, by virtue of its target being frequently and highly expressed in
triple-negative breast cancer, its activity was particularly promising in this subset of patients. Results from the clinical studies in
breast cancer as well as companion studies in
melanoma indicate that a
biomarker-informed approach is the optimal pathway for the future development of this
drug.