Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier

Abstract

ABSTRACTThe blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human antibodies across the BBB in mice can be enhanced by modulating their interactions with the neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on the antibody Fc domain, immunohistochemical assays reveal widespread distribution of the engineered antibodies throughout the mouse brain. These engineered antibodies remain specific for their antigens and retain pharmacological activity. We propose that novel brain-targeted therapeutic antibodies can be engineered to differentially engage FcRn for receptor-mediated transcytosis across the BBB in order to improve neurological disease therapeutics in the future.

Keywords

• Blood-brain barrier (BBB)
• central nervous system (CNS)
• immunoglobulin G (IgG)
• neonatal fc receptor (FcRn)
• transcytosis
• Trojan horse