Leveraging neonatal Fc receptor (FcRn) to enhance antibody transport across the blood brain barrier
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.
Authors
- Monica K Wetzel-Smith
- Daniela Bumbaca Yadav
- Hao Cai (ORCID: https://orcid.org/0000-0003-1024-647X)
- Ben Chih (ORCID: https://orcid.org/0000-0002-1248-8379)
- Shan Chung (ORCID: https://orcid.org/0000-0002-5494-2103)
- James A. Ernst
- William J. Meilandt (ORCID: https://orcid.org/0000-0002-8672-8769)
- Julien Lafrance‐Vanasse (ORCID: https://orcid.org/0000-0001-8807-6277)
- Shraddha Sadekar
- Susan Crowell (ORCID: https://orcid.org/0000-0002-8086-5981)
- Donna W. Lee (ORCID: https://orcid.org/0000-0003-1061-1385)
- Jasvinder K. Atwal (ORCID: https://orcid.org/0000-0001-5995-478X)
- Mandy Kwong
- Nguyễn Văn Hiệp (ORCID: https://orcid.org/0000-0002-3390-7923)
- Sara Francesca Santagostino (ORCID: https://orcid.org/0000-0002-0788-9303)
- Greg A. Lazar (ORCID: https://orcid.org/0000-0003-2169-8703)
- Vivian Lee (ORCID: https://orcid.org/0000-0001-5802-8899)
- Pamela Chan
- Yanli Yang (ORCID: https://orcid.org/0000-0002-3810-2761)
Institutions
- Gene Therapy Laboratory (FR)
- Bioanalytica (Switzerland) (CH)
- Research & Diagnostic Antibodies (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1038/s41467-025-59447-1
- Citations
- 12
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 16.32
Funders
- Genentech