Human Health Therapeutics Research Centre, Translational Bioscience, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada.
BioDrugs. 2018 Dec;32(6):547-559. doi: 10.1007/s40259-018-0309-y.
Antibody, immuno- and gene therapies developed for neurological indications face a delivery challenge posed by various anatomical and physiological barriers within the central nervous system (CNS); most notably, the blood-brain barrier (BBB). Emerging delivery technologies for biotherapeutics have focused on trans-cellular pathways across the BBB utilizing receptor-mediated transcytosis (RMT). 'Traditionally' targeted RMT receptors, transferrin receptor (TfR) and insulin receptor (IR), are ubiquitously expressed and pose numerous translational challenges during development, including species differences and safety risks. Recent advances in antibody engineering technologies and discoveries of RMT targets and BBB-crossing antibodies that are more BBB-selective have combined to create a new preclinical pipeline of BBB-crossing biotherapeutics with improved efficacy and safety. Novel BBB-selective RMT targets and carrier antibodies have exposed additional opportunities for re-targeting gene delivery vectors or nanocarriers for more efficient brain delivery. Emergence and refinement of core technologies of genetic engineering and editing as well as biomanufacturing of viral vectors and cell-derived products have de-risked the path to the development of systemic gene therapy approaches for the CNS. In particular, brain-tropic viral vectors and extracellular vesicles have recently expanded the repertoire of brain delivery strategies for biotherapeutics. Whereas protein biotherapeutics and bispecific antibodies enabled for BBB transcytosis are rapidly heading towards clinical trials, systemic gene therapy approaches for CNS will likely remain in research phase for the foreseeable future. The promise and limitations of these emerging cross-BBB delivery technologies are further discussed in this article.
针对神经学适应症开发的抗体、免疫和基因疗法面临着各种中枢神经系统（CNS）内的解剖学和生理学障碍带来的输送挑战；尤其是血脑屏障（BBB）。新兴的生物治疗输送技术专注于利用细胞间途径穿越 BBB，利用受体介导的胞吞作用（RMT）。“传统上”靶向 RMT 受体，转铁蛋白受体（TfR）和胰岛素受体（IR），广泛表达，并在开发过程中带来许多转化挑战，包括物种差异和安全风险。抗体工程技术的最新进展以及对 RMT 靶点和 BBB 穿越抗体的发现，这些抗体具有更高的 BBB 选择性，两者结合起来为具有更好疗效和安全性的 BBB 穿越生物治疗药物创建了一个新的临床前流水线。新型 BBB 选择性 RMT 靶点和载体抗体为重新靶向基因传递载体或纳米载体以实现更有效的大脑输送提供了更多机会。基因工程和编辑核心技术的出现和完善以及病毒载体和细胞衍生产品的生物制造已经降低了开发针对 CNS 的系统性基因治疗方法的风险。特别是，脑趋向性病毒载体和细胞外囊泡最近扩大了生物治疗药物的脑输送策略范围。尽管能够穿越 BBB 的蛋白生物治疗药物和双特异性抗体已迅速进入临床试验阶段，但在可预见的未来，针对 CNS 的系统性基因治疗方法可能仍处于研究阶段。本文进一步讨论了这些新兴的跨 BBB 输送技术的前景和局限性。
