Pardridge William M, Boado Ruben J
Department of Medicine, UCLA, Los Angeles, California, USA.
Methods Enzymol. 2012;503:269-92. doi: 10.1016/B978-0-12-396962-0.00011-2.
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.
重组蛋白疗法无法进入脑药物开发领域，因为这些大分子药物无法穿过血脑屏障（BBB）。然而，重组蛋白可以被改造为可穿透血脑屏障的IgG融合蛋白，其中IgG部分是针对内源性血脑屏障受体的基因工程单克隆抗体（MAb），例如人类胰岛素受体（HIR）或转铁蛋白受体（TfR）。IgG与内源性胰岛素受体或TfR结合，触发跨血脑屏障的转运，并作为分子特洛伊木马（MTH）将融合的蛋白治疗药物运送至脑内。迄今为止，最有效的MTH是一种针对HIR的单克隆抗体，称为HIRMAb，它在人类和旧世界灵长类动物（如恒河猴）中具有活性。目前尚无针对小鼠胰岛素受体的已知单克隆抗体。对于小鼠体内的药物递送，蛋白治疗药物与针对小鼠TfR的嵌合单克隆抗体（称为cTfRMAb）融合。HIRMAb或cTfRMAb特洛伊木马已被设计并表达为与多种类型的蛋白治疗药物的融合蛋白，包括溶酶体酶、神经营养因子、诱饵受体、单链Fv治疗性抗体和抗生物素蛋白。IgG融合蛋白的药代动力学（PK）特性与典型的单克隆抗体药物不同，由于外周组织以及脑的快速摄取，其PK谱类似于小分子。IgG融合蛋白的脑摄取量为注射剂量的2 - 3%/脑，与小分子的脑摄取量相当。IgG融合蛋白已在小鼠模型中长期给药，免疫反应滴度低，对体内融合蛋白从血液中的清除或脑摄取没有影响。血脑屏障MTH技术能够对多种重组蛋白治疗药物进行改造，以实现靶向脑内的药物递送。
