title: Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program.
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.
  
  
  METHODS
  Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/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.
authors.affiliation: A.I. duPont Hospital for Children, Wilmington, Delaware.
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Thomas
authors.initials: T
authors.lastname: Hawthorne
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; C551271:glembatumumab vedotin
keywords: antibody-drug conjugate; developmental therapeutics; osteosarcoma; preclinical testing