Bao Xuhui, Pastan Ira, Bigner Darell D, Chandramohan Vidyalakshmi
Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Receptors Clin Investig. 2016;3(4). doi: 10.14800/rci.1430.
Glioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with the Exotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins. cytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are promising.
胶质母细胞瘤是所有原发性脑肿瘤和中枢神经系统肿瘤中最具侵袭性的恶性脑肿瘤。按照当前的标准治疗方案（手术、放疗和化疗），胶质母细胞瘤患者的中位生存时间不到15个月。因此，迫切需要开发更有效的治疗方法来提高胶质母细胞瘤患者的低生存率。为满足这一需求，我们通过将D2C7单克隆抗体（mAb）的单链可变片段（scFv）与外毒素（PE38KDEL）融合，开发了一种新型的肿瘤靶向免疫毒素（IT），即D2C7-(scdsFv)-PE38KDEL（D2C7-IT）。D2C7-IT可与野生型表皮生长因子受体（EGFRwt）和EGFR变异体III（EGFRvIII）发生反应，这两种癌蛋白在胶质母细胞瘤中经常扩增或过度表达。表面等离子体共振和流式细胞术分析表明，D2C7-IT对EGFRwt和EGFRvIII蛋白均具有显著的结合能力。细胞毒性数据显示，D2C7-IT可有效抑制蛋白质合成，并杀死多种表达EGFRwt、EGFRvIII以及同时表达EGFRwt和EGFRvIII的胶质母细胞瘤异种移植细胞和人类肿瘤细胞系。此外，当通过脑内对流增强递送（CED）给药时，D2C7-IT在原位小鼠胶质瘤模型中表现出强大的抗肿瘤功效。因此，我们进行了一项临床前毒性研究，以确定D2C7-IT通过脑内CED在大鼠体内给药72小时后的最大耐受剂量（MTD）和未观察到不良反应水平（NOAEL）。基于这项成功的大鼠毒性研究，一项研究性新药（IND）申请（#116855）获得了美国食品药品监督管理局（FDA）的批准，目前一项D2C7-IT的I/II期临床试验（用于复发性恶性胶质瘤成年患者的D2C7，https://clinicaltrials.gov/ct2/show/NCT02303678）正在进行。虽然现在从该试验得出结论还为时过早，但迄今为止的结果很有希望。
