Stanimirovic Danica, Kemmerich Kristin, Haqqani Arsalan S, Farrington Graham K
Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada.
Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada.
Adv Pharmacol. 2014;71:301-35. doi: 10.1016/bs.apha.2014.06.005. Epub 2014 Aug 23.
The development and approval of antibody-based therapeutics have progressed rapidly over the past decade. However, poor blood-brain barrier (BBB) permeability hinders the progress of antibody therapies for conditions in which the target is located in the central nervous system (CNS). Increased brain penetration of therapeutic antibodies can be achieved by engineering bispecific antibodies in which one antibody binding specificity recognizes a BBB receptor that undergoes receptor-mediated transcytosis (RMT) from the circulatory compartment into brain parenchyma, and the second binding specificity recognizes a therapeutic target within the CNS. These bispecific antibodies can be built using various antibody fragments as "building blocks," including monomeric single-domain antibodies, the smallest antigen-binding fragments of immunoglobulins. The development of BBB-crossing bispecific antibodies requires targeted antibody engineering to optimize multiple characteristics of "BBB carrier" and therapeutic arms, as well as other antibody properties impacting pharmacokinetics and effector function. Whereas several BBB-crossing bispecific antibodies have been developed using transferrin receptor antibodies as BBB carriers, the principal obstacle for capitalizing on the future promise of CNS-active antibodies remains the scarcity of known, characterized RMT receptors which could be exploited for the development of BBB carriers. This chapter reviews the recent advances and guiding principles for designing, engineering, and evaluating BBB-crossing bispecific antibodies and discusses approaches to identify and characterize novel BBB-crossing antibodies and RMT receptors.
在过去十年中，基于抗体的治疗药物的研发和审批进展迅速。然而，血脑屏障（BBB）通透性差阻碍了针对靶点位于中枢神经系统（CNS）疾病的抗体疗法的发展。通过构建双特异性抗体可以提高治疗性抗体的脑渗透性，其中一种抗体结合特异性识别一种血脑屏障受体，该受体可通过受体介导的转胞吞作用（RMT）从循环系统进入脑实质，另一种结合特异性识别中枢神经系统内的治疗靶点。这些双特异性抗体可以使用各种抗体片段作为“构建模块”来构建，包括单体单域抗体，即免疫球蛋白最小的抗原结合片段。开发能够穿越血脑屏障的双特异性抗体需要有针对性的抗体工程，以优化“血脑屏障载体”和治疗臂的多种特性，以及影响药代动力学和效应功能的其他抗体特性。虽然已经开发了几种以转铁蛋白受体抗体作为血脑屏障载体的能够穿越血脑屏障的双特异性抗体，但充分利用中枢神经系统活性抗体未来前景的主要障碍仍然是已知的、已表征的可用于开发血脑屏障载体的RMT受体稀缺。本章综述了设计、构建和评估能够穿越血脑屏障的双特异性抗体的最新进展和指导原则，并讨论了鉴定和表征新型能够穿越血脑屏障的抗体和RMT受体的方法。
