title: Imaging and phase I study of 111In- and 90Y-labeled anti-LewisY monoclonal antibody B3.
abstract: B3 is a murine monoclonal antibody (mAb) that recognizes a LewisY carbohydrate antigen present on the surface of many carcinomas. An imaging and Phase I trial was performed to study the ability of 111In-mAb B3 to image known metastasis and determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), kinetics, and biodistribution of 90Y-mAb B3. Patients (n = 26) with advanced epithelial tumors that express the LewisY antigen were entered. All patients received 5 mCi of 111In-mAb B3 for imaging. 90Y-mAb B3 doses were escalated from 5 to 25 mCi in 5-mCi increments. 111In-mAb B3 and 90Y-mAb B3 were coadministered over a 1-h infusion. Definite tumor imaging was observed in 20 of 26 patients. Sites imaged included lung, liver, bone, and soft tissues. The MTD of 90Y-mAb B3 was determined to be 20 mCi. The DLTs were neutropenia and thrombocytopenia. Tumor doses ranged from 7.7 to 65.1 rad/mCi. 111In- and 90Y-mAb B3 serum pharmacokinetics (n = 23) were found to be similar. The amount of B3 administered (5, 10, and 50 mg) did not alter the pharmacokinetics. Bone marrow biopsies (n = 23) showed 0.0038+/-0.0016% of injected dose/gram for 111In-mAb B3 compared to 0.0046+/-0.0017% of injected dose/gram for 90Y-mAb B3 (P = 0.009). When given to patients with carcinomas that express the LewisY antigen, 111In-mAb B3 demonstrated good tumor localization. The MTD of 90Y-mAb B3 is 20 mCi, with myelosuppression as the DLT. Higher doses of radioactivity need to be delivered to achieve an antitumor effect. Humanized mAb B3 is being developed for evaluation in radioimmunotherapy. A clinical trial to explore the use of higher doses of 90Y-mAb B3 with autologous stem cell support is planned.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Pai-Scherf
authors.forename: J A
authors.initials: JA
authors.lastname: Carrasquillo
authors.forename: C
authors.initials: C
authors.lastname: Paik
authors.forename: O
authors.initials: O
authors.lastname: Gansow
authors.forename: M
authors.initials: M
authors.lastname: Whatley
authors.forename: D
authors.initials: D
authors.lastname: Pearson
authors.forename: K
authors.initials: K
authors.lastname: Webber
authors.forename: M
authors.initials: M
authors.lastname: Hamilton
authors.forename: C
authors.initials: C
authors.lastname: Allegra
authors.forename: M
authors.initials: M
authors.lastname: Brechbiel
authors.forename: M C
authors.initials: MC
authors.lastname: Willingham
authors.forename: I
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D011877:Radionuclide Imaging; D014018:Tissue Distribution; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D015021:Yttrium Radioisotopes