Pharmacokinetics and acute toxicology of intraventricular I-131-monoclonal antibody targeting disialoganglioside in non-human primates
Pharmacokinetics and acute toxicology of intraventricular I-131-monoclonal antibody targeting disialoganglioside in non-human primates
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DOI：
10.1023/a:1005822524905
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发表时间：
1997-11-01
影响因子：
3.9
通讯作者：
Gillio, AP
中科院分区：
文献类型：
--
作者：
Kramer, K;Cheung, NKV;Gillio, AP
转移到软脑膜的肿瘤通常是无法治愈的，尽管目前积极的治疗方式。通过鞘内施用单克隆抗体（MoAb）的区域治疗可以使其在肿瘤部位的浓度最大化，同时降低全身毒性。抗G（D2）抗体3F 8已成功靶向人神经外胚层衍生的肿瘤。人和食蟹猴中枢神经系统中的二唾液酸神经节苷脂G（D2）表达相同。我们研究了8只食蟹猴脑室内注射I-131- 3F 8的药代动力学和急性和亚急性毒性。在注射前2-4周，有目的地用静脉内施用的3F 8免疫四只动物。所有动物均保持临床稳定。毒性包括体重减轻、发热和CSF白细胞增多。1只动物在第7次注射后出现左侧轻偏瘫，推测是由于间歇性开放导管的局部药物蓄积所致。免疫猴和非免疫猴CST的辐射剂量分别为19-18戈伊和19-82戈伊，血液的辐射剂量分别为0.11-0.98戈伊和0.29-2.03戈伊。组织学检查显示2只动物的导管放置区域附近出现慢性反应性变化和局灶性血管炎。外周血细胞计数和骨髓检查保持正常。由于血脑屏障，CSF猴抗小鼠抗体滴度低于血清中的10%。与所有动物中相似的CSF放射性清除率相反，3F 8免疫动物的血液清除率相对于对照组显著加快。相应地，CSF与血液剂量比提高了1.3至6.6倍（平均3.5）。我们得出结论，在灵长类动物脑室内注射I-131- 3F 8是可以耐受的。它可以向CSF空间提供非常高剂量的辐射，对血液和骨髓的毒性最小。血清抗鼠抗体可加速血中I-131- 3F 8的清除，提高治疗指数。
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-G(D2) antibody 3F8 has successfully targeted human neuroectoderm derived tumors. Disialoganglioside G(D2) 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 I-131-3F8 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 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 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 I-131-3F8 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 I-131-3F8 in blood and may improve the therapeutic index.