title: L1-CAM-targeted antibody therapy and (177)Lu-radioimmunotherapy of disseminated ovarian cancer.
abstract: The L1-cell adhesion molecule (L1-CAM) is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1-CAM and exhibits anti-proliferative effects on L1-CAM-expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel (177)Lu-chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth-inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl, an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10-tetraazacyclododecane-N-N'-N'-N‴-tetraacetic acid (DOTA) and labeled with the low-energy β-emitter (177)Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 μg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of (177)Lu-chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 ± 8.1% ID/g at 168 h postinjection. A single treatment with (177)Lu-DOTA-chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted (177)Lu-immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of (177)Lu-DOTA-chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1-CAM.
authors.affiliation: Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Grünberg
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohn
authors.forename: Karin
authors.initials: K
authors.lastname: Waldner-Knogler
authors.forename: Simone
authors.initials: S
authors.lastname: Jeger
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Ilse
authors.initials: I
authors.lastname: Novak-Hofer
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008187:Lutetium / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000628:therapy*; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D039842:Neural Cell Adhesion Molecule L1; D008187:Lutetium