Neonatal Fc receptor and its role in the absorption, distribution, metabolism and excretion of immunoglobulin G-based biotherapeutics.

The neonatal Fc receptor (FcRn) is a heterodimeric membrane associated protein expressed in a variety of endothelial, epithelial and hematopoietic cells. FcRn regulates pH dependent intracellular trafficking of immunoglobulin G (IgG) and albumin, resulting in enhanced serum persistence and transcellular permeability of these proteins compared to other proteins of similar size. FcRn confers passive immunity during the early stages of life by facilitating maternal transmission of antibodies during gestation, and in some species during the neonatal period. The receptor continues to contribute to immunity beyond the perinatal period and throughout life by providing immunosurveillance in intestinal, pulmonary and genitourinary mucosa. In this capacity, FcRn facilitates bidirectional transport of IgG across mucosa and intracellular trafficking of antigen-antibody complexes in antigen presenting cells. Based on the functional roles of FcRn in regulating serum persistence and transcellular permeability, protein engineers have sought to exploit this receptor as a means of enhancing the absorption, distribution, metabolism and excretion (ADME) of IgG-based therapeutics. In this review, the current state of knowledge regarding the structural, mechanistic and functional properties of FcRn, as they relate to the ADME of IgG-based therapeutics, are discussed.