Distribution of FcRn Across Species and Tissues

Abstract

The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I type molecule that binds to, transports, and recycles immunoglobulin G (IgG) and albumin, thereby protecting them from lysosomal degradation. Therefore, besides the knowledge of FcRn affinity, FcRn protein expression is critical in understanding the pharmacokinetic behavior of Fc-containing biotherapeutics such as monoclonal antibodies. The goal of this investigation was to achieve for the first time a comparative assessment of FcRn distribution across a variety of tissues and species. FcRn was mapped in about 20 tissues including placenta from human and the most frequently used species in non-clinical safety testing of monoclonal antibodies (mouse, rat, cynomolgus monkey). In addition, the FcRn expression pattern was characterized in two humanized transgenic mouse lines (Tg32 and Tg276) expressing human FcRn under different promoters, and in the severe combined immunodeficient (SCID) mouse. Consecutive sections were stained with specific markers, namely, anti-CD68 for macrophages and anti-von Willebrand Factor for endothelial cells. Overall, the FcRn expression pattern was comparable across species and tissues with consistent expression of FcRn in endothelial cells and interstitial macrophages, Kupffer cells, alveolar macrophages, enterocytes, and choroid plexus epithelium. The human FcRn transgenic mouse Tg276 showed a different and much more widespread staining pattern of FcRn. In addition, immunodeficiency and lack of IgG in SCID mice had no negative effect on FcRn expression compared with wild-type mice.

Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides

“…Given the expression of FcRn in multiple tissues (including those involved in clearance such as liver and kidneys), the receptor has the potential to have various roles in the tissue distribution of mAbs and peptides. A few studies have been conducted in which the expression of FcRn in various tissues and species including humanized transgenic mouse lines was examined (Garg and Balthasar, 2007;Chen et al, 2014;Yip et al, 2014;Fan et al, 2016;Latvala et al, 2017). A comprehensive comparative assessment of FcRn distribution in ;20 tissues from humans and nonclinical species (rat, mouse, cynomolgus monkeys, two humanized transgenic mouse lines, and the severe combined immunodeficient mouse) showed FcRn was expressed in endothelial cells and interstitial macrophages, Kupffer cells, alveolar macrophages, enterocytes, and choroid plexus epithelium (Latvala et al, 2017).…”

“…A few studies have been conducted in which the expression of FcRn in various tissues and species including humanized transgenic mouse lines was examined (Garg and Balthasar, 2007;Chen et al, 2014;Yip et al, 2014;Fan et al, 2016;Latvala et al, 2017). A comprehensive comparative assessment of FcRn distribution in ;20 tissues from humans and nonclinical species (rat, mouse, cynomolgus monkeys, two humanized transgenic mouse lines, and the severe combined immunodeficient mouse) showed FcRn was expressed in endothelial cells and interstitial macrophages, Kupffer cells, alveolar macrophages, enterocytes, and choroid plexus epithelium (Latvala et al, 2017). In addition, in these studies the FcRn expression pattern was similar across each species with the exception of the human FcRn transgenic mouse Tg276 (Latvala et al, 2017).…”

Breastmilk cell trafficking induces microchimerism‐mediated immune system maturation in the infant

“…The duration of FcRn expression on the neonatal gastrointestinal tract varies between mammalian species and, for many, occurs at weaning—but, by contrast, much earlier in human infants. Rodents and many other mammals depend exclusively on this transport mechanism for prolonged periods to maintain adequate levels of IgG in blood . For example, maternal immunity is mediated exclusively by colostral Ig in ruminants .…”

“…Rodents and many other mammals depend exclusively on this transport mechanism for prolonged periods to maintain adequate levels of IgG in blood. 13,26,27 For example, maternal immunity is mediated exclusively by colostral Ig in ruminants. 28 FcRn are present on the luminal surface of proximal small intestine enterocytes.…”

Evaluation of an Fcrn Affinity Chromatographic Method for Igg1-Type Antibodies and Evaluation of Igg Variants

“…Nevertheless, changes in FcRn binding measured by SPR did not correlate well with changes in serum half-life [14]. Until recently, the pH-dependent dissociation from FcRn was not covered by suitable in vitro assays but could be captured accurately by respective pharmacokinetic (PK) m easurements in huFcRn-transgenic mice [15,16].…”