Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program

E. Anders Kolb, Richard Gorlick, Catherine A. Billups, Thomas Hawthorne, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Background: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. Procedures: Glembatumumab vedotin was administered intravenously at a dose of 2.5mg/kg using a weekly×3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. Results: Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P<0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. Conclusions: Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels.

Original languageEnglish (US)
Pages (from-to)1816-1821
Number of pages6
JournalPediatric Blood and Cancer
Volume61
Issue number10
DOIs
StatePublished - Oct 2014

Keywords

  • Antibody-drug conjugate
  • Developmental therapeutics
  • Osteosarcoma
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Kolb, E. A., Gorlick, R., Billups, C. A., Hawthorne, T., Kurmasheva, R. T., Houghton, P. J., & Smith, M. A. (2014). Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program. Pediatric Blood and Cancer, 61(10), 1816-1821. https://doi.org/10.1002/pbc.25099