title: Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2-SN-38 Antibody Conjugate (Sacituzumab Govitecan).
abstract: OBJECTIVE
  This study examined the delivery of SN-38 to Trop-2-expressing tumors and assessed the constitutive products in the serum, liver, and small intestine in nude mice bearing human tumor xenografts (Capan-1 or NCI-N87) given a single injection of irinotecan (40 mg/kg; ∼ 0.8 mg/mouse, containing ∼ 460 μg SN-38 equivalents) or sacituzumab govitecan (IMMU-132), an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG coupled site specifically with an average of 7.6 molecules of SN-38.
  
  
  METHODS
  At select times, tissues were extracted and concentrations of the products measured by reversed-phase high-performance liquid chromatography (HPLC).
  
  
  RESULTS
  In serum, >98% irinotecan cleared within 5 minutes; peak levels of SN-38 and SN-38G (glucuronidated SN-38) were detected in equal amounts at this time, and no longer detected after 6 to 8 hours. IMMU-132 was detected in the serum over 3 days, and at each interval, ≥ 95% of total SN-38 was bound to the antibody. Intact IMMU-132 cleared with a half-life of 14 hours, which closely reflected the in vitro rate of SN-38 released from the conjugate in mouse serum (i.e., 17.5 hours), whereas the IgG portion of the conjugate cleared with a half-life of 67.1 hours. In vitro and in vivo studies disclosed IgG-bound SN-38 was protected from glucuronidation. Area under the curve (AUC) analysis indicated that IMMU-132 delivers 20-fold to as much as 136-fold more SN-38 to tumors than irinotecan, with tumor:blood ratios favoring IMMU-132 by 20- to 40-fold. Intestinal concentrations of SN-38/SN-38G also were 9-fold lower with IMMU-132.
  
  
  CONCLUSIONS
  These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan.
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Serengulam V
authors.initials: SV
authors.lastname: Govindan
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000951:Antigens, Neoplasm / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D000077146:Irinotecan; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; C499380:TACSTD2 protein, human; D000077146:Irinotecan; C000608132:sacituzumab govitecan; D002166:Camptothecin