Glembatumumab vedotin, also known as CDX-011 or CR011-vcMMAE, is a fully-human monoclonal antibody-drug conjugate 0r ADC designed to target the glycoprotein NMB (gpNMB). [1]
GPNMB, a negative prognostic marker, is a protein over-expressed (defined as expression in > 25% of tumor cells) by multiple tumor types, including breast cancer and melanoma. GPNMB expression in the tumor epithelium has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and a reduction in disease-free and overal survival in breast cancer.[4]
The GPNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream. Following internalization of MMAE into GPNMB-expressing tumor cells – which breaks the linkage between mAb and the payload drug – results in a targeted cell-killing effect.
Structure
CR011 is a fully human IgG2 monoclonal antibody. In glembatumumab vedotin, the mAb is linked to the potent microtubule inhibitor MMAE via a cathepsin cleavable valine-citrulline (vc) dipeptide linker. [1]
Clinical development
Glembatumumab vedotin is being developed by Celldex, Inc for the treatment of locally advanced or metastatic breast cancer—with an initial focus in triple negative breast cancer. This program is also in development for the treatment of Stage III and IV melanoma.
Results from the Emerge trial show that glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%) participating in this trial, activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial called METRIC) MEtastatic TRIple-Negative Breast Cancer) was initiated in December 2013. [2]
The METRIC trial is designed to evaluating glembatumumab vedotin in patients with GPNMB over-expressing triple negative breast cancer. This study is a direct comparison of glembatumumab vedotin versus capecitabine (Xeloda®; Genentech/Roche). The primary endpoint for this study is progression free survival.[3]
Click here for more information about current and pas clinical trials for glembatumumab vedotin.
Adverse events
In clinical trials skin rash was the most commonly reported toxicity. Researchers believe that this may be caused by the (limited) expression of GPNMB in healthy skin. Furthermore, glembatumumab vedotin had a relatively short t(1/2). This prompts the evaluation of more frequent dosing schedules.
Last Editorial Review: September 1, 2015
