Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer

Glembatumumab vedotin (CR-011-vc-MMAE) is a mAb-drug conjugate being developed by Celldex Therapeutics Inc for the treatment of glycoprotein non-metastatic melanoma protein B (GPNMB)-expressing cancers. Glembatumumab is a fully human mAb directed against an extracellular domain of GPNMB expressed in human breast cancers and melanomas. Glembatumumab is conjugated to the potent microtubule inhibitor monomethyl Auristatin E using a Cathepsin cleavable valine-citrulline (vc) dipeptide linker. Glembatumumab vedotin has demonstrated potent antitumor activity in preclinical studies, including in GPNMB-expressing cell lines. In human melanoma xenograft mice, intravenous glembatumumab vedotin was associated with complete tumor regression without significant toxicity. In two phase I/II clinical trials, intravenous glembatumumab vedotin demonstrated antitumor activity in patients with breast Cancer or melanoma. Skin rash was the most common toxicity reported, which may have been caused by the expression of GPNMB in healthy skin. Glembatumumab vedotin had a relatively short t(1/2) , prompting the evaluation of more frequent dosing schedules. Prospective, randomized clinical trials will likely be required to determine the therapeutic potential of glembatumumab vedotin in the treatment of breast Cancer and melanoma.