title: Pharmacokinetics and acute toxicology of intraventricular 131 I-monoclonal antibody targeting disialoganglioside in non-human primates.
abstract: Tumors metastatic to the leptomeninges are often incurable despite current aggressive treatment modalities. Regional therapy by intrathecal administration of monoclonal antibodies (MoAbs) can maximize their concentration to tumor sites while reducing systemic toxicities. Anti-GD2 antibody 3F8 has successfully targeted human neuroectoderm derived tumors. Disialoganglioside GD2 expression in the central nervous system is identical between humans and cynomolgus monkeys. We studied the pharmacokinetics and the acute and subacute toxicities of intraventricular 131I-3F8 in 8 cynomolgus monkeys. Four animals were purposely immunized with intravenous 3F8 administered 2-4 weeks prior to injections. All animals remained clinically stable. Toxicities included weight loss, fever and CSF leukocytosis. One animal developed a left-sided hemiparesis following his seventh injection, presumably due to a local drug accumulation in the setting of an intermittently patent catheter. The estimated radiation dose to the CSF was 19-48 Gy in the immunized monkeys and 19-82 Gy in the nonimmunized monkeys, and to blood was 0.11-0.98 Gy and 0.29-2.03 Gy, respectively. Histopathology revealed chronic reactive changes adjacent to the region of catheter placement and a focal vasculitis in 2 animals. Peripheral blood counts and bone marrow examinations remained normal. Because of the blood-brain barrier, CSF monkey-anti-mouse antibody titers were less than 10 per cent of those in the serum. In contrast to the CSF radioactivity clearance which was similar in all animals, blood clearance was substantially accelerated in 3F8-immunized animals versus controls. Correspondingly, the CSF to blood dose ratio was improved 1.3 to 6.6 fold (mean 3.5). We conclude that intraventricular administration of 131I-3F8 in primates is tolerable. It can deliver very high doses of radiation to the CSF space with minimal toxicity to blood and bone marrow. Serum anti-mouse antibody accelerates the clearance of 131I-3F8 in blood and may improve the therapeutic index.
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kramer
authors.forename: N K
authors.initials: NK
authors.lastname: Cheung
authors.forename: J
authors.initials: J
authors.lastname: Humm
authors.forename: G
authors.initials: G
authors.lastname: DiResta
authors.forename: E
authors.initials: E
authors.lastname: Arbit
authors.forename: S
authors.initials: S
authors.lastname: Larson
authors.forename: R
authors.initials: R
authors.lastname: Finn
authors.forename: M
authors.initials: M
authors.lastname: Rosenblum
authors.forename: H
authors.initials: H
authors.lastname: Nguyen
authors.forename: G
authors.initials: G
authors.lastname: Gonzalez
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: Y F
authors.initials: YF
authors.lastname: Yang
authors.forename: M E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: A P
authors.initials: AP
authors.lastname: Gillio
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001921:Brain / Q000378:metabolism*; D002408:Catheters, Indwelling; D005732:Gangliosides / Q000493:pharmacokinetics* / Q000633:toxicity; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes; D016014:Linear Models; D008252:Macaca fascicularis; D008297:Male; D011829:Radiation Dosage; D012016:Reference Values
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007457:Iodine Radioisotopes; C025447:sialogangliosides