利用新生儿Fc受体（FcRn）增强抗体穿越血脑屏障的转运。

Leveraging neonatal Fc receptor (FcRn) to enhance antibody transport across the blood brain barrier.

作者信息

Lafrance-Vanasse Julien, Sadekar Shraddha S, Yang Yanli, Yadav Daniela Bumbaca, Meilandt William J, Wetzel-Smith Monica K, Cai Hao, Crowell Susan R, Nguyen Van, Lee Vivian, Chih Ben, Kwong Mandy, Chan Pamela, Santagostino Sara, Lee Donna, Chung Shan, Lazar Greg A, Ernst James A, Atwal Jasvinder K

机构信息

Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, 94080, USA.

Department of Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, CA, 94080, USA.

出版信息

Nat Commun. 2025 May 3;16(1):4143. doi: 10.1038/s41467-025-59447-1.

DOI:10.1038/s41467-025-59447-1

PMID:40319060

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12049489/

Abstract

The blood-brain barrier (BBB) restricts efficient penetration of systemically delivered therapeutic antibodies into the brain, limiting the development of this class of drugs to treat neurodegenerative diseases. Here we demonstrate that the neonatal Fc receptor (FcRn), which is highly expressed at the BBB, can be used to facilitate IgG transport to the brain. Engineering of the antibody Fc region to promote binding to FcRn at neutral pH enhances antibody transcytosis in a cellular model. In vivo, these modifications improve brain penetration, as well as brain target engagement and activity, of systemically administered antibodies in both mice and non-human primates. This engineering approach can be broadly implemented to enhance central nervous system (CNS) exposure of antibody- and Fc-based drugs, improving the clinical potential of biotherapeutics for the treatment of human brain diseases.

摘要

血脑屏障（BBB）限制了全身给药的治疗性抗体有效渗透进入大脑，这限制了这类用于治疗神经退行性疾病的药物的开发。在此，我们证明在血脑屏障高度表达的新生儿Fc受体（FcRn）可用于促进IgG转运至大脑。对抗体Fc区进行工程改造以促进其在中性pH下与FcRn结合，可增强细胞模型中的抗体转胞吞作用。在体内，这些修饰改善了全身给药抗体在小鼠和非人灵长类动物中的脑渗透以及脑靶向结合和活性。这种工程方法可广泛应用于增强基于抗体和Fc的药物在中枢神经系统（CNS）中的暴露，提高生物治疗药物治疗人类脑部疾病的临床潜力。