Abstract C207: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of Glembatumumab Vedotin.
Authors: Gorlick Richard , Kolb Anders , Wu Jainrong , Kurmasheva Raushan , Hawthorne Thomas , Houghton Peter , Smith Malcolm 
Published: August 2014

Abstract
Introduction: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin, dc-HIL, and HGFIN). Because of the restrictive expression of GPNMB, testing was limited to the PPTP osteosarcoma (OS) xenograft panel as well as two non-GPNMB expressing rhabdomyosarcoma (RMS) xenografts.
Methods: Glembatumumab vedotin was administered intravenously in 0.9% saline at a dose of 2.5 mg/kg using a weekly x 3 schedule. GPNMB was assessed at the RNA level (Agilent SurePrint3) and by IHC.
Results: All of the six OS xenografts against which glembatumumab vedotin was tested expressed GPNMB at the RNA level as evaluated using Agilent gene expression arrays. By contrast, none of the RMS xenografts expressed GPNMB at the RNA level. Most OS xenografts showed GPNMB expression detectable by IHC (6/7), while none of the RMS xenografts showed tumor staining for GPNMB (0/6).
Glembatumumab vedotin was well tolerated, and all 8 tested xenograft models were considered evaluable for efficacy. For the OS xenografts, glembatumumab vedotin induced significant differences in EFS distribution compared to control in each of the 6 models studied. Three of 6 OS xenografts showed maintained complete responses (MCR) to glembatumumab vedotin. Two other xenografts showed progressive disease with growth delay (PD2), with one of these showing near stable disease during the 6 weeks of treatment and observation. The final OS xenograft showed progressive disease with no growth delay (PD1). As expected, the two RMS xenografts showed limited responses to glembatumumab vedotin (PD1 and PD2), although one did show significant tumor growth inhibition with an EFS T/C value of 2.6.
Two of the OS xenografts with MCR showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB gene expression had the poorest response to glembatumumab vedotin. For GPNMB protein expression assessed by IHC, 2 of the xenografts with MCR showed the highest expression level and highest percent tumor expression, but the other responding line showed GPNMB expression on only 5% of tumor cells, despite exhibiting one of the highest expression levels of GPNMB by mRNA. The two OS xenograft lines least responsive to glembatumumab vedotin were also the least responsive OS xenografts to vincristine and eribulin.
Conclusions: Glembatumumab vedotin showed high-level activity against 3 of 6 OS xenografts. Response of OS xenografts to glembatumumab vedotin may be related to both GPNMB expression and to the intrinsic susceptibility of xenografts to tubulin inhibitors. RMS xenografts showed PD1 or PD2 responses to glembatumumab vedotin despite having known sensitivity to tubulin-binding agents such as eribulin. Glembatumumab vedotin is the first antibody-drug conjugate with documented in vivo activity against OS. (Supported by NO1-CM-42216)
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C207.
Citation Format: Richard Gorlick, Anders Kolb, Jainrong Wu, Raushan Kurmasheva, Thomas Hawthorne, Peter Houghton, Malcolm Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of Glembatumumab Vedotin. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C207.