Chapter 4 Multitasking by Exploitation of Intracellular Transport Functions

Abstract

The MHC Class I-related receptor, FcRn, transports antibodies of the immunoglobulin G (IgG) class within and across a diverse array of different cell types. Through this transport, FcRn serves multiple roles throughout adult life that extend well beyond its earlier defined function of transcytosing IgGs from mother to offspring. These roles include the maintenance of IgG levels and the delivery of antigen in the form of immune complexes to degradative compartments within cells. Recent studies have led to significant advances in knowledge of the intracellular trafficking of FcRn and (engineered) IgGs at both the molecular and cellular levels. The engineering of FcRn–IgG (or Fc) interactions to generate antibodies of increased longevity represents an area of active interest, particularly in the light of the expanding use of antibodies in therapy. The strict pH dependence of FcRn–IgG interactions, with binding at pH 6 that becomes essentially undetectable as near neutral pH is approached, is essential for efficient transport. The requirement for retention of low affinity at near neutral pH increases the complexity of engineering antibodies for increased half-life. Conversely, engineered IgGs that have gained significant binding for FcRn at this pH can be potent inhibitors of FcRn that lower endogenous IgG levels and have multiple potential uses as therapeutics. In addition, molecular studies of FcRn–IgG interactions indicate that mice have limitations as preclinical models for FcRn function, primarily due to cross-species differences in FcRn-binding specificity.

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

“…Moreover, FcRn was shown to be involved in IgG transport across the feto-maternal barrier and across endothelial and epithelial cellular barriers increasing their overall bioavailability. 15,16 This property has been successfully exploited for pulmonary delivery, as well as intranasal immunization with Fc-fusion proteins. 17,18 Lastly, FcRn was also reported to transport IgGantigen complexes, thus favoring antigen-presentation, [19][20][21] and to enable phagocytosis of IgG-opsonized bacteria by neutrophils, 22 demonstrating a wide range of functions for this receptor in several immunological and non-immunological mechanisms.…”

The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics

“…These analyses result in an understanding, in spatiotemporal terms, of the effect of pH dependence of antibody-antigen interactions on subcellular trafficking and inform the design of antibodies with optimized binding properties for antigen elimination. 4,13,[18][19][20] Consequently, there is interest in developing antibodies that can both neutralize their soluble target in the extracellular environment and release bound antigen into a degradative pathway following uptake into cells. 11,12,21 Interleukin-6 (IL-6) is a secreted 26-kDa pleiotropic, proinflammatory cytokine produced by multiple cell types.…”

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

“…The long half-life of IgG1 and its ability to bind FcgRs as well as C1q have made it attractive as an Ab therapeutic. The long half-life relies on its interaction with the neonatal Fc receptor (FcRn) (19,20).…”