ArmaGen, Inc., 26679 Agoura Road, Calabasas, CA, 91302, USA.
BioDrugs. 2017 Dec;31(6):503-519. doi: 10.1007/s40259-017-0248-z.
Biologics are potential new therapeutics for many diseases of the central nervous system. Biologics include recombinant lysosomal enzymes, neurotrophins, decoy receptors, and therapeutic antibodies. These are large molecule drugs that do not cross the blood-brain barrier (BBB). All classes of biologics have been tested, without success, in clinical trials of brain disease over the last 25 years. In none of these past clinical trials was the biologic re-engineered to enable transport across the BBB. If the biologic does not cross the BBB, the drug cannot reach the target site in brain, and success in a clinical trial is not expected. Biologics can be re-engineered for BBB transport with the use of molecular Trojan horse technology. A BBB molecular Trojan horse is a monoclonal antibody (MAb) against an endogenous BBB receptor transporter, such as the insulin receptor or transferrin receptor. The receptor-specific MAb penetrates the brain via transport on the endogenous BBB receptor. The MAb acts as a molecular Trojan horse to deliver across the BBB the biologic pharmaceutical that is genetically fused to the MAb. The lead Trojan horse is a MAb against the human insulin receptor (HIR), and HIRMAb-derived fusion proteins have entered clinical trials for the treatment of brain disease.
生物制剂是治疗中枢神经系统多种疾病的潜在新疗法。生物制剂包括重组溶酶体酶、神经营养因子、诱饵受体和治疗性抗体。这些都是大分子药物，不能穿过血脑屏障（BBB）。在过去 25 年的脑部疾病临床试验中，所有类别的生物制剂都经过了测试，但都没有成功。在这些过去的临床试验中，没有一种生物制剂经过重新设计以使其能够穿过 BBB。如果生物制剂不能穿过 BBB，药物就无法到达大脑中的靶部位，临床试验也不会成功。生物制剂可以通过使用分子木马技术进行 BBB 转运的重新设计。BBB 分子木马是针对内源性 BBB 受体转运蛋白的单克隆抗体（MAb），例如胰岛素受体或转铁蛋白受体。受体特异性 MAb 通过内源性 BBB 受体的转运穿透大脑。MAb 充当分子木马，将与 MAb 基因融合的生物制药递送到 BBB 之外。领先的木马是针对人胰岛素受体（HIR）的 MAb，并且 HIR MAb 衍生的融合蛋白已进入治疗脑部疾病的临床试验。
