Neonatal Fc receptor and IgG-based therapeutics

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…FcRn is essential for the stability (halflife) of the antibody in vivo and for the regulation of IgG levels in serum. 28,29 Indeed, the FcRn receptor is present on epithelial cells, endothelial cells, monocytes and/or macrophages, and leading to maturation and activation of specific effector CTL (Fig. 1C).…”

“…Recirculation of mAbs and transcytosis through FcRn are important mechanisms of mAb stabilization in vivo and distribution across tissues, respectively. [28][29][30] Thus, Fc modifications aimed at improving bioavailability and/or stability of therapeutic mAbs in vivo are being actively sought by several groups, even though a considerable amount of work is still required to define the best strategies and translate the laboratory findings into the clinic. Indeed, improved binding at acid pH does not necessarily translate into longer half-life and better bioavailability.…”

“…Indeed, improved binding at acid pH does not necessarily translate into longer half-life and better bioavailability. 29,30 Finally, RTX can bind to C1q and activate the classical complement cascade. C1q is a protein complex composed of 18 peptides that form 6 identical globular heads on a single stem structure (often compared with a bunch of tulips).…”

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

“…10 In addition to increasing mAbs cytotoxicity, extensive efforts have also been made to improve mAbs pharmacokinetic (PK) properties. 11,12 Despite the relatively long half-lives of mAbs, improved molecules with longer half-lives and conserved efficacy would permit less frequent dosing schedules and provide higher patient convenience. IgG half-life is dependent on the neonatal Fc receptor (FcRn), a member of the MHC class I superfamily, which is expressed by many cell types including endothelial cells, macrophages, monocytes and monocyte-derived dendritic cells in human.…”

Oral nanoparticles

“…2,3 FCRN normally functions to transport maternal IgG from breast milk to offspring; however, receptor expression persists in the adult intestines and is also present in tissues including the blood brain barrier, liver, lungs, vascular endothelium and kidneys. 4,5 A team from The University of Nottingham had previously shown that peptides bound to FCRN could be transported across the airway epithelium. 6 Next, the Brigham and Women's Hospital team conjugated the Fc portion of IgG, which binds FCRN, to the surface of standard polylactic acid (PLA)-polyethylene glycol (PEG) nanoparticles using maleimide linkers.…”