Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Institute of Clinical Medicine, Department of Pharmacology, University of Oslo, Oslo, Norway.
Nat Commun. 2024 Mar 7;15(1):2007. doi: 10.1038/s41467-024-46321-9.
Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.
单克隆 IgG 抗体构成了增长最快的治疗药物类别。因此，人们强烈希望设计更有效的抗体形式，其中长血浆半衰期是具有商业竞争力的差异化因素，影响剂量、给药频率，从而可能影响患者的依从性。在这里，我们报告了一种 Fc 工程变体，该变体具有三个氨基酸取代 Q311R/M428E/N434W（REW），可提高血浆半衰期和粘膜分布，并允许在人类 FcRn 转基因小鼠中通过无针方式穿越呼吸上皮屏障。此外，Fc 工程变体可改善针对靶细胞的补体介导的癌细胞杀伤作用，以及革兰氏阳性菌和革兰氏阴性菌。因此，这种多功能 Fc 技术应该在旨在进行长效预防性或治疗性干预的抗体设计中得到广泛应用。
