Bao Xuhui, Chandramohan Vidyalakshmi, Reynolds Randall P, Norton John N, Wetsel William C, Rodriguiz Ramona M, Aryal Dipendra K, McLendon Roger E, Levin Edward D, Petry Neil A, Zalutsky Michael R, Burnett Bruce K, Kuan Chien-Tsun, Pastan Ira H, Bigner Darell D
Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.
Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
Invest New Drugs. 2016 Apr;34(2):149-58. doi: 10.1007/s10637-015-0318-3. Epub 2016 Jan 4.
D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.
D2C7-(scdsFv)-PE38KDEL（D2C7-IT）是一种新型免疫毒素，可与胶质母细胞瘤中过表达的野生型表皮生长因子受体（EGFRwt）和突变型EGFRvIII蛋白发生反应。本研究评估了脑内给予D2C7-IT的毒性，以支持美国食品药品监督管理局（FDA）的首个新药临床试验申请。在优化制剂和给药方式后，将两个队列（一个急性队列和一个慢性队列，分别在研究第5天和第34天进行尸检）的Sprague-Dawley（SD）大鼠（每组5只雄性和5只雌性，共四组）通过渗透泵经脑内对流增强给药，以0、0.05、0.1、0.4μg（急性队列）和0、0.05、0.1、0.35μg（慢性队列）的总剂量输注D2C7-IT制剂约72小时。在每个队列的0.40μg（5/10只大鼠）和0.35μg（4/10只大鼠）高剂量组中观察到死亡。仅在高剂量D2C7-IT治疗的大鼠中出现体重减轻和行为异常。两个队列的临床实验室检查均未观察到剂量相关效应。对两个队列中高剂量组和对照组的全身组织进行大体病理学检查，未发现剂量相关或药物相关的病理学发现。脑组织病理学显示，两个队列的高剂量组中经常出现剂量相关的脑软化、水肿和脱髓鞘。在本研究中，确定D2C7-IT在SD大鼠中的最大耐受剂量为0.10至0.35μg，未观察到不良反应水平为0.05μg。这两个参数均用于设计D2C7-IT的I/II期临床试验。
