The Versatile MHC Class I-related FcRn Protects IgG and Albumin from Degradation: Implications for Development of New Diagnostics and Therapeutics

Abstract

The half-life of the two most abundant proteins in blood, immunoglobulin G (IgG) and serum albumin, is extraordinary (approximately 19-23 days) compared to other circulating proteins. This phenomenon secures a broad biodistribution throughout the body of both molecules. The long half-life has made IgG the natural choice for engineering of antibody based therapeutics, while albumin is used as a fusion partner for or carrier of drugs. Remarkably, the half-life of these unrelated proteins has been shown prolonged by a receptor recycling pathway mediated by a common cell bound receptor named the neonatal Fc receptor (FcRn). This review summarizes our current understanding of FcRn function and discusses its relevance for development of new IgG and albumin based therapeutics and diagnostics.

Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain

“…The use of albumin fusion or albumin binding for the purpose of extending the serum half-life of short lived molecules has been extensively described previously (25,49,50). However, no reports have so far addressed the impact of such fusion or targeting in relation to pH-dependent binding to FcRn.…”

“…Animals (n ϭ 3 at each time point) were sacrificed at 0. 25,4,20,48,72,168, and 240 h post-injection, by means of intravenous pentobarbital. Samples of blood, hind leg muscle, and skin, as well as whole liver and kidneys, were excised and weighed, and radioactivity was measured using an automatic ␥-spectrometer (1480 Wizard, Wallac Oy, Turku, Finland).…”

“…Because FcRn is a bifunctional receptor that binds IgG and albumin simultaneously and rescues both proteins from intracellular degradation (25)(26)(27), the impact of ABD on shFcRn binding to IgG was also investigated. Human-mouse chimeric IgG1 with specificity for the hapten NIP (hIgG1 NIP ) was captured on NIP-conjugated BSA coated in MaxiSorp wells.…”

“…In addition to having a molecular size above the renal clearance threshold, the long half-lives are attributed to the efficient receptor-mediated recycling pathway involving the neonatal Fc receptor (FcRn) (25)(26)(27). FcRn is a major histocompatibility class I-related protein that resides predominantly within acidified endosomes of endothelial and hematopoietic cells (28 -31).…”

Structural Insights into Neonatal Fc Receptor-based Recycling Mechanisms

“…It interacts in a pH-dependent fashion with SA or IgG molecules so that the strength of the corresponding interactions ranges from highest at acidic pH to lowest around neutral pH (4 -8). This remarkable property is critical to recycling IgG and SA from within acidic endosomes back to the general circulation and allows their rescue from a degradative pathway (7)(8)(9)(10), thereby prolonging their serum half-life.…”