title: A phase I radioimmunolocalization trial of humanized monoclonal antibody huA33 in patients with gastric carcinoma.
abstract: In order to determine the in vivo characteristics of huA33, an open label dose escalation biopsy-based phase I clinical trial and radioimmunolocalization study were conducted with a complement determinant region-grafted humanized monoclonal antibody against the A33 antigen in patients with gastric carcinoma. Thirteen patients were entered onto one of four dose levels (1.0, 2.0, 5.0 or 10.0 mg/m(2)). Patients with locally advanced (UICC-TNM [International Union Against Cancer-tumor, node, metastasis] stage over 2 but resectable at clinical diagnosis) gastric carcinoma received a single infusion of (131)I-huA33 1 week prior to surgery. Adverse events were monitored, and imaging studies with gamma camera plus ex vivo scintigraphy of the resected specimen, biodistribution study by dosimetry analysis of the biopsied and resected tissues, and immunohistochemical analysis were carried out and evaluated. No dose-limiting toxicity was observed during the trial. Therefore, the maximum tolerated dose was not reached. Although cancer tissues with + intensity and <25% extent by immunostaining in biopsied frozen sections did not show positive imaging or postoperative dosimetry findings, cancers with ++ or +++ intensity or wide (>25%) extent by frozen and paraffin sections in the biopsied specimen showed positive ex vivo tumor images and positive antigen expression in resected gastric cancer specimens, and the biodistribution analysis showed tumor uptake of (131)I-huA33. In conclusion, humanized monoclonal antibody huA33 demonstrated selective localization to gastric cancer that expressed A33 antigen strongly. These excellent targeting characteristics of huA33 indicate potential for targeted therapy of advanced gastric cancer that is refractory to cytotoxic therapy, and could also be exploitable for curatively resected early gastric cancer in an adjuvant setting.
authors.affiliation: Department of Epidemiological and Clinical Research Information Management, Kyoto University, Kyoto 606-8501, Japan. sakamoto@pbh.med.kyoto-u.ac.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Oriuchi
authors.forename: Erito
authors.initials: E
authors.lastname: Mochiki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asao
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hoffman
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: F T
authors.initials: FT
authors.lastname: Lee
authors.forename: Anthony
authors.initials: A
authors.lastname: Papenfuss
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takahashi
authors.forename: Keigo
authors.initials: K
authors.lastname: Endo
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C104258:GPA33 protein, human; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins