Neonatal Fc Receptor: From Immunity to Therapeutics

Abstract

The neonatal Fc receptor (FcRn), also known as the Brambell receptor and encoded by Fcgrt, is a MHC class I like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional antigen presenting cells. Its function is evident in early life in the transport of IgG from mother to fetus and neonate for passive immunity and later in the development of adaptive immunity and other functions throughout life. The unique ability of this receptor to prolong the half-life of IgG and albumin has guided engineering of novel therapeutics. Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn.

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

“…Site-directed mutagenesis studies show how modulated binding of IgGs to FcRs or C1q can alter their biological effect. 5,32,40,70,[77][78][79] Because our characterization of the CODV format documents the excellent conservation of the properties of natural IgG, we anticipate that these mutations equivalently affect CODV-Ig functionalities, and that multi-parametric drug optimizations benefit from such mutations.…”

“…As a consequence, they may have extended serum half-lifes by endocytic salvage via neonatal FcR (FcRn), which may compensate for slow tissue penetration. [30][31][32][33][34][35] Furthermore, they may elicit antibody-dependent cell-mediated cytotoxicity or phagocytosis (ADCC or ADCP, respectively) via Fcg receptors (FcgRs), which is important for cancer biotherapeutics. 3,[36][37][38][39] Fully functional Fc domains may also confer the potential to trigger the classical pathway of complementdependent humoral response, and thereby elicit complementdependent cytotoxicity (CDC).…”

Neonatal Fc receptor and IgG-based therapeutics

“…Detailed review of the biology of FcRn function has also been covered elsewhere. [7][8][9] Soon after the cloning of FcRn, the crystal structure of FcRnIgG interaction was resolved by Pam Bjorkman and colleagues at the California Institute of Technology who had previously resolved the crystal structure of the MHC class I molecule. The crystal structure studies revealed that two FcRn molecules bind to a single IgG with 2:1 stoichiometry, FcRn-Fc binding was pH dependent with minimal conformational change, and the critical contact sites identified on both molecules were later confirmed by surface plasmon resonance approach.…”

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…IgG half-life is dependent on the neonatal Fc receptor (FcRn), a member of the MHC class I superfamily, which is expressed by many cell types including endothelial cells, macrophages, monocytes and monocyte-derived dendritic cells in human. 13,14 FcRn is a high affinity Fc receptor that binds IgG in a strictly pH-dependent manner. IgGs are internalized by non-specific pinocytosis into the endosomes of cells where the low pH (pH 5-6) promotes binding to FcRn with nanomolar affinity.…”