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FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes


, : FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes. Plos One 10(4): E0124930-E0124930

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and into circulation, enabling the elongated half-life of rFVIIIFc.

US$19.90

PMID: 25905473

DOI: 10.1371/journal.pone.0124930


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Tatsumi, Y.; Harada, A.; Matsumoto, T.; Tani, T.; Nishida, H., 2009: Current status and evaluation of transnasal esophagogastroduodenoscopy. We reviewed the current status of transnasal esophagogastroduodenoscopy (EGD) with regard to tolerance, safety, feasibility and accuracy. Comparison of standard and ultrathin scopes and recently reported endoscopic techniques with transnasal inser...

Volkov E.M.; Poletaev G.I., 1982: Nonquantum release of acetyl choline in the frog myo neural junction after axoplasmic transport blockade with colchicine. Standard microelectrode techniques were used to evaluate the effect of d-tubocurarine chloride on membrane potential of junctional and extrajunctional areas of muscle fibers in a K-free Ringer solution. The experiments were made on frogs [Rana rid...

Hara, T.; Kato, H.; Katsube, Y.; Oda, J., 1996: A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution. The crystal structure of glutathione synthetase from Escherichia coli B complexed with ADP, glutathione, and sulfate has been determined at 2.0 ANG resolution. Concerning the chemical similarity of sulfate and phosphate, this quaternary complex st...

Li, L.; Zhang, P-Yang.; Ran, H.; Dong, J.; Fang, L-Ling.; Ding, Q-Shan., 2017: Evaluation of left ventricular myocardial mechanics by three-dimensional speckle tracking echocardiography in the patients with different graded coronary artery stenosis. To investigate the relationship between left ventricular (LV) myocardial mechanics evaluated by three-dimensional speckle tracking echocardiography (3D-STE) and degree of coronary artery stenosis in patients with coronary artery disease (CAD). Nin...

Balaraman, N.; Venkatakrishnan, R., 1974: Nutritive value of sunnhemp (Crotalaria juncea Linn) for hay for sheep. Three Mandya rams were used in a metabolism trial to study the nutritive value of sunnhemp hay as the only roughage for sheep. Palatability was poor as the stems were mostly rejected but of the portions eaten palatabilty was good. To meet maintena...

Varney Mark S.; Turner David R.; Whitfield Michael; Mantoura Richard F.C., 1984: The use of electrochemical techniques to monitor complexation capacity titrations in natural waters. 1: 33-46 1984

Fauquet, C.M.; Maxwell, D.P.; Gronenborn, B.; Stanley, J., 2000: Revised proposal for naming geminiviruses. A system for naming geminiviruses is presented, and a list of geminiviruses together with suggested names is provided.

Gochfeld, M.; Volz, C.D.; Burger, J.; Jewett, S.; Powers, C.W.; Friedlander, B., 2006: Developing a health and safety plan for hazardous field work in remote areas. Developing health and safety plans (HASPs) is a common feature of occupational safety and health for many workplaces. Formal HASPs are a requirement for hazardous waste work, requiring the anticipation and identification of hazards and embodying...

Segre, Riccardo, 1927: Further studies on the sino-auricular node. In the fetal and adult horse the auricu- lar (Keith-Flack) node is double, having a right and left part. These 2 masses are not connected by any specific musculature. The investigator suggests that the doubling of the sino-auricular node in the ho...

Rasmussen J.B., 1985: A new species of crotaphopeltis from east africa with remarks on the identity of dipsas hippocrepis serpentes boiginae. C. braestrupi sp. nov. is described from Somalia and northern Kenya. The new species is distinguished on lepidosis, dentition, internal morphology and especially the very long hemipenis. C. hippocrepis (Reinhardt, 1843) comb. nov. (Dipsas hippocre...