PHARMACOKINETICS AND ACUTE TOXICOLOGY OF INTRAVENTRICULAR I-131 MONOCLONAL-ANTIBODY TARGETING DISIALOGANGLIOSIDE IN NONHUMAN-PRIMATES

Tumors metastatic to the leptomeninges are often incurable despite cur rent aggressive treatment modalities. Regional therapy by intrathecal administration of monoclonal antibodies (MoAbs) can maximize their con centration to tumor sites while reducing systemic toxicities. Anti-G(D 2) antibody 3F8 has successfully targeted human neuroectoderm derived tumors. Disialoganglioside G(D2) expression in the central nervous sys tem is identical between humans and cynomolgus monkeys. We studied the pharmacokinetics and the acute and subacute toxicities of intraventri cular I-131-3F8 in 8 cynomolgus monkeys. Four animals were purposely i mmunized with intravenous 3F8 administered 2-4 weeks prior to injectio ns. All animals remained clinically stable. Toxicities included weight loss, fever and CSF leukocytosis. One animal developed a left-sided h emiparesis 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 CST was 19-18 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 chr onic reactive changes adjacent to the region of catheter placement and a focal vasculitis in 2 animals. Peripheral blood counts and bone mar row examinations remained normal. Because of the blood-brain barrier, CSF monkey-anti-mouse antibody titers were less than 10 per cent of th ose in the serum. In contrast to the CSF radioactivity clearance which was similar in all animals, blood clearance was substantially acceler ated in 3F8-immunized animals versus controls. Correspondingly, the CS F to blood dose ratio was improved 1.3 to 6.6 fold (mean 3.5). We conc lude that intraventricular administration of I-131-3F8 in primates is tolerable. It can deliver very high doses of radiation to the CSF spac e with minimal toxicity to blood and bone marrow. Serum anti-mouse ant ibody accelerates the clearance of I-131-3F8 in blood and may improve the therapeutic index.