Centre for Immune Regulation (CIR) and Department of Immunology, University of Oslo and Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.
Institute of Clinical Medicine and Department of Pharmacology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway.
Sci Transl Med. 2020 Oct 14;12(565). doi: 10.1126/scitranslmed.abb0580.
Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.
无针吸收穿过黏膜屏障是生物制剂给药的首选途径，但非辅助性跨黏膜转运的效率很差。为了使管理和治疗有效和方便，生物制剂的传递策略必须增强细胞内传递和血浆半衰期。我们发现，人白蛋白通过依赖于新生 Fc 受体 (FcRn) 的机制有效地穿过极化的人上皮细胞。FcRn 也转运免疫球蛋白 G，但转运量是白蛋白的两倍。因此，我们设计了一种人白蛋白变体 E505Q/T527M/K573P（QMP），其与 FcRn 的结合得到了改善，从而在转染表达人 FcRn 的转基因小鼠中，鼻内给药时增强了细胞内转运，并延长了白蛋白的血浆半衰期。当 QMP 与重组激活凝血因子 VII 融合时，与野生型人白蛋白融合相比，融合分子的半衰期增加了 3.6 倍，而不影响激活因子 VII 的治疗特性。我们的发现强调了 QMP 作为蛋白质生物制剂的合适载体，它可能会延长血浆半衰期并穿过黏膜屏障进行传递。
