The role of Fc-receptors in the uptake and transport of therapeutic antibodies in the retinal pigment epithelium

Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation

“…Together with the observation that after intravitreal injection bevacizumab was present in REC of wild-type mice but not in those of FcRn −/− mice, these findings strongly support the hypothesis that the Fc domain primarily destines the fate of an intravitreally injected protein and that the FcRn plays a crucial role in this process [39]. An FcRn-dependent transport of aflibercept through cells of the RPE was also observed [8]. In these cells, aflibercept is co-localized with the motor protein myosin 7a and with proteins of the cytoskeleton (→ actin), indicating a similar though not identical behavior of the Fc fusion protein in the two different cell types forming the outer and inner blood retina barrier.…”

“…After intravitreal injection into the mammalian eye, aflibercept, which contains an Fc (fragment crystallizable) domain, was detected in ocular structures including retinal vessels and the retinal pigment epithelium (RPE), implying at least partial clearance of aflibercept via the posterior route [3–5]. Accordingly, retinal endothelial cells (REC) or cells of the RPE take up aflibercept in vitro, and transcellular transport through these types of cells was observed [6–8]. A carrier protein likely involved in shuttling IgG and other Fc-containing polypeptides is the neonatal Fc receptor/transporter (FcRn), which indeed is expressed in various parts of the eye including the retinal endothelium and cultivated REC [9–12].…”

Role of the Fc Region in the Vitreous Half-Life of Anti-VEGF Drugs

“…Some reports showed that inhibition of FcRn increased apical to choroidal transport of bevacizumab, indicating a role of FcRn in the recycling of the molecule. 12 Another study showed that protein molecular weight and Fc region did not play critical roles in ocular PK as they do systemically. 22 According to our results, VEGF-Trap showed Fc region-dependent properties in ocular PK.…”

“…FcRn is vital for increasing the serum circulating half-life of antibodies and for protecting them from lysosomal degradation. 12 Hence, it is an important factor in systemic PK of antibodies. However, the function of FcRn in intraocular PK was not reported until recently, when studies showed the presence of FcRn on RPE cells; moreover, recent studies showed that FcRn, which is involved in intracellular uptake and transport of Fc-containing molecules in the retina, played an essential role in eliminating intravitreally administered IgGs across the blood-retina barrier into the systemic circulation.…”

“…10 Recent studies reported that the elimination of intravitreally administered IgG across the blood-retina barrier into the systemic circulation is mediated by the neonatal Fc receptor (FcRn), which is expressed in the retinal pigment epithelium and endothelial cells of the retinal and choroidal vasculature. [11][12][13] Ocular application of the Fcbased fusion proteins is a relatively new advance, and whether their elimination or transport depends on FcRn and/or the molecular weight remains unclear. Understanding of the role of the Fc region and FcRn in intraocular pharmacokinetics (PK) is important in determining the duration of therapeutic efficacy of drugs as well as in anticipating the systemic exposure of intravitreally injected anti-VEGF agents, which can potentially cause systemic complications.…”