Clinical Ramifications of the MHC Family Fc Receptor FcRn

Abstract

Introduction-Knowledge that antibodies of the IgG isotype have remarkably extended persistence in circulation and are able to pass through cell barriers has substantial implications. While is well-established that so-called neonatal Fc receptor, FcRn, acts throughout life to confer these unusual properties, its ramifications on clinical medicine and therapeutic uses are not broadly appreciated.

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

“…Engineering interaction with FcRn gives control over the pharmacokinetic/pharmacodynamic profiles of biotherapeutic drugs, whether linear or non-linear pharmacokinetics will determine clearance. 29,33,34,69,70 Thereby administration and dosing strategy can be tailored in function of disease requirements, which may differ widely in chronic and ad-hoc treatments. Systematic pharmacokinetic studies show that increased FcRn affinity leads to increased elimination half-life of IgGs; however, modulation of in vitro affinity does not result in predictive modification of the in vivo elimination profile.…”

“…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).…”

Immunoglobulin Transport and Immunoglobulin Receptors

“…Among these are its widespread tissue distribution, ability to prolong the half-life of molecules with IgG Fc regions, and capacity for shuttling such molecules across tissue boundaries. Advancements in molecular biology techniques enabling the generation of fusion proteins containing IgG Fc regions coupled with a growing understanding of the detailed molecular interactions that enable FcRn-IgG binding are leading to the expansion of Fc-based therapeutic strategies that rely critically on FcRn handling for their kinetic properties and effectiveness (Kuo et al, 2010;Roopenian and Sun, 2010). Fusion of a therapeutic agent to an IgG Fc region is known to enhance the half-life of the therapeutic owing to FcRn-mediated protection from catabolism; this has important implications for the frequency of delivery and dosage of the drug needed for effective treatment.…”

Maternal Genital Tract Infection

“…During 17-22 weeks, the IgG levels are only about 5-10% of the maternal levels but reach 50% of maternal levels by 32-33 weeks' gestation, which partially explains some of the increased susceptibility to infection experienced by premature infants in the first few months of life (reviewed in Palmiera et al, 2012). At term, fetal IgG concentrations can exceed maternal IgG by 20-30%, with the sharpest increase occurring after 36 weeks (Roopenian and Akilesh, 2007; reviewed in Roopenian and Sun, 2010). However, even full-term infants who have received a full complement of maternal transplacental IgG can still have an increased susceptibility to infections, especially those that the mother has not previously encountered.…”