title: AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma.
abstract: OBJECTIVE
  New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy.
  
  
  METHODS
  Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood.
  
  
  RESULTS
  ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell-cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death.
  
  
  CONCLUSIONS
  AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial.
authors.affiliation: Agensys Inc., Santa Monica, California. fdonate@agensys.com.
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Arthur
authors.initials: A
authors.lastname: Raitano
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Kendall
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Zili
authors.initials: Z
authors.lastname: An
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Linnette
authors.initials: L
authors.lastname: Capo
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Hector
authors.initials: H
authors.lastname: Aviña
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Sher
authors.initials: S
authors.lastname: Karki
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Morrison
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Ou
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Moriya
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Shostak
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Faisal
authors.initials: F
authors.lastname: Malik
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Rossana
authors.initials: R
authors.lastname: Nadell
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Wendy
authors.initials: W
authors.lastname: Liu
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Daulet
authors.initials: D
authors.lastname: Satpayev
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: John
authors.initials: J
authors.lastname: Atkinson
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Ingrid B J
authors.initials: IB
authors.lastname: Joseph
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pereira
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Challita-Eid
authors.affiliation: Agensys Inc., Santa Monica, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Stover
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001491:Basophils / Q000187:drug effects / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008252:Macaca fascicularis; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C427944:ENPP3 protein, human; D018796:Immunoconjugates; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases