title: ING-1, a monoclonal antibody targeting Ep-CAM in patients with advanced adenocarcinomas.
abstract: OBJECTIVE
  To determine the feasibility of administration, safety, toxicity, immunogenicity, pharmacokinetics, maximum tolerated dose, and biodistribution of ING-1, a high-affinity, Human-Engineered monoclonal antibody (heMAb) to the Mr 40,000 epithelial cell adhesion molecule Ep-CAM, in patients with advanced adenocarcinomas.
  
  
  METHODS
  ING-1 was initially administered to patients as a 1-hour intravenous infusion every 3 weeks. Toxicity and pharmacokinetic data led to the evaluation of a weekly schedule. The distribution of iodine-131 (131I)-labeled ING-1 was studied.
  
  
  RESULTS
  Twenty-five patients received 82 courses of ING-1. Minimal toxicity was initially observed at the 0.03-, 0.10-, and 0.30-mg/kg dose levels. A patient dosed at 1.0 mg/kg developed acute pancreatitis with severe abdominal pain, nausea, and vomiting. A patient dosed at 0.3 mg/kg had an asymptomatic amylase and lipase elevation to 502 units/L and 1,627 units/L, respectively. Both patients made uncomplicated recoveries. No other dose-limiting toxicities were observed. Regardless of dose, the volume of distribution (mean +/- SEM) was 46.6 +/- 1.6 mL/kg. ING-1 clearance decreased with increasing dose. To minimize toxicity and increase dose intensity, we then administered ING-1 weekly. No significant toxicity was observed in 7 patients dosed at 0.1 mg/kg. Studies of 131I-labeled ING-1 biodistribution showed radiolocalization to colorectal and prostate cancers. A patient with colorectal cancer had an 80% decrement in the levels of carcinoembryonic antigen.
  
  
  CONCLUSIONS
  The recommended dose for ING-1 is 0.10 mg/kg by intravenous infusion weekly. The absence of severe toxicity at this dose, low immunogenicity, and preliminary evidence of ING-1 tumor localization and antitumor efficacy support the further clinical development of this antibody to treat Ep-CAM-positive malignant diseases.
authors.affiliation: Institute For Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA. johanndebono@hotmail.com
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Andre
authors.initials: A
authors.lastname: Forero
authors.forename: Gertrude F A
authors.initials: GF
authors.lastname: Vanhove
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bauer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Mark L
authors.initials: ML
authors.lastname: White
authors.forename: Sui
authors.initials: S
authors.lastname: Shen
authors.forename: Muhammad B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D019540:Area Under Curve; D001835:Body Weight; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C479480:ING-1 monoclonal antibody, human