title: Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody-Drug Conjugate as a Therapeutic for Non-Small Cell Lung and Ovarian Cancers.
abstract: OBJECTIVE
  Antibody-drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium-phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.
  
  
  METHODS
  The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non-small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.
  
  
  RESULTS
  We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.
  
  
  CONCLUSIONS
  Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments.
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Kedan
authors.initials: K
authors.lastname: Lin
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Bonnee
authors.initials: B
authors.lastname: Rubinfeld
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Crystal
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Harstad
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Leslie
authors.initials: L
authors.lastname: Roth
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Siao Ping
authors.initials: SP
authors.lastname: Tsai
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.affiliation: Genentech Research and Early Development, South San Francisco, California. polakis.paul@gene.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051381:Rats; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000037:antagonists & inhibitors / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D009842:Oligopeptides; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; C495575:monomethyl auristatin E