Heyen Jonathan R, Rojko Jennifer, Evans Mark, Brown Tom P, Bobrowski Walter F, Vitsky Allison, Dalton Shana, Tripathi Niraj, Bollini Sangeetha Subbarao, Johnson Theodore, Lin John C, Khan Nasir, Han Bora
Drug Safety Research & Development, Pfizer Inc, San Diego, California, USA
Charles River Pathology Associates, Frederick, Maryland, USA.
Toxicol Pathol. 2014 Jun;42(4):765-73. doi: 10.1177/0192623314522559. Epub 2014 Mar 10.
Two 6-month repeat-dose toxicity studies in cynomolgus monkeys illustrated immune complex-mediated adverse findings in individual monkeys and identified parameters that potentially signal the onset of immune complex-mediated reactions following administration of RN6G, a monoclonal antibody (mAb). In the first study, 3 monkeys exhibited nondose-dependent severe clinical signs accompanied by decreased erythrocytes with increased reticulocytes, neutrophilia, monocytosis, thrombocytopenia, coagulopathy, decreased albumin, azotemia, and increased serum levels of activated complement products, prompting unscheduled euthanasia. Histologically, immunohistochemical localization of RN6G was associated with monkey immunoglobulin and complement components in glomeruli and other tissues, attributable to immune complex disease (ICD). All 3 animals also had anti-RN6G antibodies and decreased plasma levels of RN6G. Subsequently, an investigational study was designed and conducted with regulatory agency input to detect early onset of ICD and assess reversibility to support further clinical development. Dosing of individual animals ceased when biomarkers of ICD indicated adverse findings. Of the 12 monkeys, 1 developed anti-RN6G antibodies and decreased RN6G exposure that preceded elevations in complement products, interleukin-6, and coagulation parameters and decreases in albumin and fibrinogen. All findings in this monkey, except for antidrug antibody (ADA), reversed after cessation of dosing without progressing to adverse sequelae typically associated with ICD.
两项针对食蟹猴的6个月重复给药毒性研究表明，个别猴子出现了免疫复合物介导的不良发现，并确定了一些参数，这些参数可能预示着在给予单克隆抗体（mAb）RN6G后免疫复合物介导反应的开始。在第一项研究中，3只猴子表现出与剂量无关的严重临床症状，伴有红细胞减少、网织红细胞增多、中性粒细胞增多、单核细胞增多、血小板减少、凝血障碍、白蛋白降低、氮质血症以及血清中活化补体产物水平升高，导致提前实施安乐死。组织学检查显示，RN6G的免疫组化定位与肾小球和其他组织中的猴免疫球蛋白及补体成分相关，这归因于免疫复合物疾病（ICD）。所有3只动物还具有抗RN6G抗体，且血浆中RN6G水平降低。随后，在监管机构的参与下设计并开展了一项研究，以检测ICD的早期发作并评估其可逆性，以支持进一步的临床开发。当ICD的生物标志物显示不良发现时，停止对个别动物给药。在12只猴子中，有1只在补体产物、白细胞介素-6和凝血参数升高以及白蛋白和纤维蛋白原降低之前就产生了抗RN6G抗体，且RN6G暴露减少。这只猴子的所有发现，除了抗药物抗体（ADA）外，在停药后均恢复正常，未发展为通常与ICD相关的不良后遗症。
