Targeting FcRn for the modulation of antibody dynamics

Abstract

The MHC Class I-related receptor, FcRn, is a multitasking protein that transports its IgG ligand within and across cells of diverse origins. The role of this receptor as a global regulator of IgG homeostasis and transport, combined with knowledge of the molecular details of FcRn-IgG interactions, has led to opportunities to modulate the in vivo dynamics of antibodies and their antigens through protein engineering. Consequently, the generation of half-life extended antibodies has shown a rapid expansion over the past decade. Further, FcRn itself can be targeted by inhibitors to induce decreased levels of circulating IgGs, which could have applications in multiple clinical settings. The engineering of antibody-antigen interactions to reduce antibody-mediated buffering of soluble ligand has also developed into an active area of investigation, leading to novel antibody platforms designed to lead to more effective antigen clearance. Similarly, the target-mediated elimination of antibodies by internalizing, membrane bound antigens (receptors) can be decreased using novel engineering approaches. These strategies, combined with subcellular trafficking analyses of antibody/antigen/FcRn behavior in cells to predict in vivo behavior, have considerable promise for the production of next generation therapeutics and diagnostics.

Pharmacokinetic properties of IgG and various Fc fusion proteins in mice

“…Finally, differences might already occur during endocytosis via non-specific fluid-phase pinocytosis and intracellular sorting by separate recycling pathways. 21,[26][27][28] In summary, our results further underline the unique pharmacokinetic properties of IgG in comparison to different Fc fusion proteins comprising an identical Fc region and also identical variable domains, and for some of the molecules that are also similar in size. Differences in dissociation from bound FcRn at neutral pH can be correlated with a reduced half-life.…”

In vivo imaging with antibodies and engineered fragments

“…Swiercz et al showed that an injection of Abdegs 8 hours after administration of 124 I-pertuzumab decreased background and improved tumor-to-blood ratios. The authors also note that the faster clearance time of the labeled probe decreased the levels of radioactivity exposure, an important consideration in clinical practice (Swiercz et al, 2014; Ward et al, 2015). …”

Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions

“…The molecular weight of 150 kDa exceeds the renal clearance threshold of 70 kDa and prevents the protein from being eliminated via the kidney. Additionally, the interaction with the neonatal Fc receptor leads to a continuous recycling process [29].…”