ME：“分子特洛伊木马”可帮助药物透过血脑屏障

脑部血管内皮细胞之间的相互连接非常紧密，这是制药产业在研发神经系统疾病新药过程中难以逾越的障碍之一。血脑屏障在阻止对具有潜在危害的有毒物质进入脑内的同时也将小分子或大分子药物拒之脑外。

哥伦比亚大学大脑研究所的WilliamPartridge博士开发出了一种能使药物分子穿过血脑屏障的方法，此项研究成果引起了伯林格因格海姆风投基金、赛尔公司、泰克达风投有限公司和三井全球投资有限公司的投资兴趣，其中的三井公司为ArmaGen技术公司在A股市场为该公司注入了近1700万美元市值的股票。

总部位于加利福尼亚桑塔莫尼卡的ArmaGen公司开发的溶液可将单克隆抗体、重组蛋白和非病毒类基因与可穿越血脑屏障的膜转运蛋白相连接。这种新型溶液就是该公司所宣传的分子特洛伊木马，可将药物分子安全地运送至脑内目标受体。

创办于8年前的ArmaGen公司从成立至今总共吸收了总计近2000万美元非对冲基金的投资。根据公司规划，新募集的资金将用于扩张公司经营规模和脑脊髓疾病治疗药物的临床研究。

起初，该公司将该技术用于称为粘多糖贮积病（MPS）罕见病的治疗上，此病有两种分型，分别为I型和II型。其中的I型也称为Hurler氏综合征，此病是一种进行性疾病，可引起儿童学习能力障碍、脊柱发育畸形、听力功能丧失以及心脏瓣膜疾病。II型也称为Hunter氏综合征，该病表现为因粘多糖在体内积聚而造成的多器官系统损害。

在应用于临床治疗前，ArmaGen公司已经在灵长类动物身上进行了该溶液的毒理学研究。该公司也做了该药用于阿尔茨海默症、抑郁症、中风、帕金森症之类疾病治疗的临床前研究。

但是ArmaGen也只是使药物透过血脑屏障诸多方法中的一种。将药物通过鼻腔内给药装置给药与Kurve技术公司发明并推动的对神经系统药物采用化学结构修饰或增强透膜能力而使药物分子透过血脑屏障有异曲同工之效。

多名医药市场分析人士预言，可透过血脑屏障药物销售额将在近期有快速增长。BCC研究认为，由ArmaGen和Angiochem引领的这类药物载体转运技术在2015年将得到快速发展。

与血脑屏障相关的拓展阅读：

• ME：“分子特洛伊木马”可帮助药物透过血脑屏障
• 首次证实HCV也能感染血脑屏障的内皮细胞
更多信息请点击：有关血脑屏障更多资讯

DOI:10.1016/B978-0-12-396962-0.00011-2,
PMC:
PMID:

Reengineering Biopharmaceuticals for Targeted Delivery Across the Blood–Brain Barrier

William M. Pardridge*, Ruben J. Boado*, †

Recombinant protein therapeutics cannot enter brain drug development because these large molecule drugs do not cross the blood–brain barrier (BBB). However, recombinant proteins can be reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a genetically engineered monoclonal antibody (MAb) against an endogenous BBB receptor, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The IgG binds the endogenous insulin receptor or TfR to trigger transport across the BBB and acts as a molecular Trojan horse (MTH) to ferry into brain the fused protein therapeutic. The most potent MTH to date is a MAb against the HIR, designated the HIRMAb, which is active in humans and Old World primates, such as the Rhesus monkey. There is no known MAb against the mouse insulin receptor. For drug delivery in the mouse, protein therapeutics are fused to a chimeric MAb against the mouse TfR, designated the cTfRMAb. The HIRMAb or cTfRMAb Trojan horses have been engineered and expressed as fusion proteins with multiple classes of protein therapeutics, including lysosomal enzymes, neurotrophins, decoy receptors, single chain Fv therapeutic antibodies, and avidin. The pharmacokinetic (PK) properties of the IgG fusion proteins differ from that of typical MAb drugs and resemble the PK profiles of small molecules due to rapid uptake by peripheral tissues, as well as brain. The brain uptake of the IgG fusion proteins, 2–3% of injected dose/brain, is comparable to the brain uptake of small molecules. The IgG fusion proteins have been administered chronically in mouse models, and the immune response is low titer and has no effect on the fusion protein clearance from blood or brain uptake in vivo. The BBB MTH technology enables the reengineering of a wide spectrum of recombinant protein therapeutics for targeted drug delivery to the brain.