Pharmacokinetics and acute toxicology of intraventricular 131I-monoclonal antibody targeting disialoganglioside in non-human primates

• Published in: Journal of neuro-oncology 1997-11, Vol.35 (2), p.101-111
• Main Authors: KRAMER, K, CHEUNG, N.-K. V, LIU, C, YANG, Y.-F, MENDELSOHN, M. E, GILLIO, A. P, HUMM, J, DIRESTA, G, ARBIT, E, LARSON, S, FINN, R, ROSENBLUM, M, NGUYEN, H, GONZALEZ, G
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Blood-brain barrier; Bone marrow; Catheters; Central nervous system; Cerebrospinal fluid; Fever; Immunotherapy; Medical sciences; Metastases; Monoclonal antibodies; Paresis; Peripheral blood; Pharmacokinetics; Pharmacology. Drug treatments; Radioactivity; Toxicity; Tumors
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1023/A:1005822524905

Tumors metastatic to the leptomeninges are often incurable despitecurrent aggressive treatment modalities. Regional therapy by intrathecaladministration of monoclonal antibodies (MoAbs) can maximize theirconcentration to tumor sites while reducing systemic toxicities.Anti-GD2 antibody 3F8 has successfully targeted humanneuroectoderm derived tumors. Disialoganglioside GD2expression in the central nervous system is identical between humans andcynomolgus monkeys. We studied the pharmacokinetics and the acute andsubacute toxicities of intraventricular 131I-3F8 in 8cynomolgus monkeys. Four animals were purposely immunized with intravenous3F8 administered 2–4 weeks prior to injections. All animals remainedclinically stable. Toxicities included weight loss, fever and CSFleukocytosis. One animal developed a left-sided hemiparesis following hisseventh injection, presumably due to a local drug accumulation in thesetting of an intermittently patent catheter. The estimated radiation doseto the CSF was 19–48 Gy in the immunized monkeys and 19–82 Gy inthe nonimmunized monkeys, and to blood was 0.11–0.98 Gy and0.29–2.03 Gy, respectively. Histopathology revealed chronic reactivechanges adjacent to the region of catheter placement and a focal vasculitisin 2 animals. Peripheral blood counts and bone marrow examinations remainednormal. Because of the blood-brain barrier, CSF monkey-anti-mouse antibodytiters were less than 10 per cent of those in the serum. In contrast to theCSF radioactivity clearance which was similar in all animals, bloodclearance was substantially accelerated in 3F8-immunized animals versuscontrols. Correspondingly, the CSF to blood dose ratio was improved 1.3 to6.6 fold (mean 3.5). We conclude that intraventricular administration of131I-3F8 in primates is tolerable. It can deliver very highdoses of radiation to the CSF space with minimal toxicity to blood and bonemarrow. Serum anti-mouse antibody accelerates the clearance of131I-3F8 in blood and may improve the therapeutic index.