Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
J Drug Target. 2010 Apr;18(3):157-67. doi: 10.3109/10611860903548354.
Biopharmaceuticals are large molecule drugs that do not cross the blood-brain barrier (BBB). The limiting factor in the drug development of biopharmaceuticals as new drugs for the human brain is the engineering of effective brain drug targeting technology platforms. Recombinant proteins, enzymes, and monoclonal antibodies can be re-engineered for transport across the human BBB with the molecular Trojan horse technology. The most active BBB molecular Trojan horse is a monoclonal antibody to the human insulin receptor. The genetic engineering of IgG fusion proteins has been demonstrated for neurotrophic factors, decoy receptors, therapeutic enzymes, single chain Fv antibodies, and avidin. The IgG fusion proteins are not toxic on repeated administration in high doses to primates and do not interfere with glycemic control in plasma or brain. IgG fusion proteins contain amino acid sequences that induce immune tolerance, and show low immunogenicity in primates. The IgG fusion proteins are new bifunctional biopharmaceuticals that are both targeted to brain via transport on endogenous BBB receptors, and exert pharmacological effects in brain at the cognate receptor, ligand, or enzyme substrate.
生物制药是不能穿透血脑屏障（BBB）的大分子药物。将生物制药作为治疗人脑的新药进行开发的限制因素在于有效脑部药物靶向技术平台的工程设计。利用分子木马技术，可以对重组蛋白、酶和单克隆抗体进行重新设计，以使其能够穿过人体 BBB。最活跃的 BBB 分子木马是针对人类胰岛素受体的单克隆抗体。已经证明，神经生长因子、诱饵受体、治疗性酶、单链 Fv 抗体和亲和素的 IgG 融合蛋白的基因工程具有靶向性。在对灵长类动物进行高剂量重复给药时，IgG 融合蛋白没有毒性，也不会干扰血浆或大脑中的血糖控制。IgG 融合蛋白包含诱导免疫耐受的氨基酸序列，在灵长类动物中具有低免疫原性。IgG 融合蛋白是新型的双功能生物制药，它们通过内源性 BBB 受体的转运靶向大脑，并在大脑中通过同源受体、配体或酶底物发挥药理作用。
