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Tommy Li, Joseph P Balthasar
Quantitative real-time PCR and Western blot methods were developed to assess neonatal Fc-receptor (FcRn) mRNA and protein expression in human FcRn transgenic mice, Swiss Webster mice, and in select human tissues. Additionally, FcRn turnover was evaluated via pulse-chase. FcRn mRNA expression was significantly higher in transgenic mice when compared to mouse FcRn mRNA in Swiss Webster mice and it ranged from 184-fold higher in the kidney to 109,000-fold higher in the skin. FcRn protein expression was found to be 13-fold lower in kidney to 5...
October 15, 2018: Biomolecules
Diana Cadena Castaneda, Christine Dhommée, Thomas Baranek, Emilie Dalloneau, Laurie Lajoie, Alexandre Valayer, Christophe Arnoult, Marie-Véronique Demattéi, Delphine Fouquenet, Christelle Parent, Nathalie Heuzé-Vourc'h, Valérie Gouilleux-Gruart
The neonatal Fc receptor (FcRn) is responsible for the recycling and transcytosis of IgG and albumin. FcRn level was found altered in cancer tissues and implicated in tumor immunosurveillance and neoplastic cell growth. However, the consequences of FcRn down-regulation in the anti-tumor immune response are not fully elucidated. By using the B16F10 experimental lung metastasis model in an FcRn-deficient microenvironment (FcRn-/- mice), we found lung metastasis associated with an abnormal natural killer (NK) cell phenotype...
2018: Frontiers in Immunology
Jeannette Nilsen, Malin Bern, Kine Marita Knudsen Sand, Algirdas Grevys, Bjørn Dalhus, Inger Sandlie, Jan Terje Andersen
Albumin has a serum half-life of three weeks in humans and is utilized to extend the serum persistence of drugs that are genetically fused or conjugated directly to albumin or albumin-binding molecules. Responsible for the long half-life is FcRn that protects albumin from intracellular degradation. An in-depth understanding of how FcRn binds albumin across species is of importance for design and evaluation of albumin-based therapeutics. Albumin consists of three homologous domains where domain I and domain III of human albumin are crucial for binding to human FcRn...
October 2, 2018: Scientific Reports
Deni Hardiansyah, Chee Meng Ng
In this study, we developed a first minimal physiologically-based pharmacokinetic (mPBPK) model to investigate the complex interaction effects of endocytosis rate/FcRn binding affinity at both acidic/physiological pH on the pharmacokinetics (PK) of the anti-VEGF IgG1 antibodies. The data used in this study were the PK of the native IgG and humanized anti-VEGF IgG1 antibodies with a wide range FcRn-binding at both acidic and physiological pH in the cynomolgus monkey. The basic structure of the developed mPBPK models consisted of plasma, tissue and lymph compartments...
September 21, 2018: European Journal of Pharmaceutical Sciences
Dennis R Goulet, Michael J Watson, Susan H Tam, Adam Zwolak, Mark L Chiu, William M Atkins, Abhinav Nath
The serum half-life and clearance of therapeutic monoclonal antibodies (mAbs) are critical factors that impact their efficacy and optimal dosing regimen. The pH-dependent binding of a mAb to the neonatal Fc receptor (FcRn) has long been recognized as an important determinant of its pharmacokinetics. However, FcRn affinity alone is not a reliable predictor of mAb half-life, suggesting that other biological or biophysical mechanisms must be accounted for. mAb thermal stability, which reflects its unfolding and aggregation propensities, may also relate to its pharmacokinetic properties...
September 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Fernando Aranda, Kariman Chaba, Norma Bloy, Pauline Garcia, Chloé Bordenave, Isabelle Martins, Gautier Stoll, Antoine Tesniere, Guido Kroemer, Laura Senovilla
The immune system avoids oncogenesis and slows down tumor progression through a mechanism called immunosurveillance. Nevertheless, some malignant cells manage to escape from immune control and form clinically detectable tumors. Tetraploidy, which consists in the intrinsically unstable duplication of the genome, is considered as a (pre)-cancerous event that can result in aneuploidy and contribute to oncogenesis. We previously described the fact that tetraploid cells can be eliminated by the immune system. Here, we investigate the role of different innate and acquired immune effectors by inoculating hyperploid cancer cells into wild type or mice bearing different immunodeficient genotypes ( Cd1d -/- , FcRn -/- , Flt3l -/- , Foxn1 nu/nu , MyD88 -/- , Nlrp3- / - , Ighm tm1Cgn , Rag2 -/- ), followed by the monitoring of tumor incidence, growth and final ploidy status...
2018: Oncoimmunology
Abhishek Saxena, Bingxin Bai, Shin-Chen Hou, Lianlian Jiang, Tianlei Ying, Shane Miersch, Sachdev S Sidhu, Donghui Wu
The therapeutic efficacy of an antibody drug depends on the variable domains and on the constant crystallizable fragment (Fc). IgG variable domains have been the targets of extensive molecular engineering in search of more specific binders with higher affinities for their targets. Similarly, Fc engineering approaches have led to modulating both the immune effector responses and serum half-lives of therapeutic antibodies. A high-affinity interaction between the IgG Fc and neonatal Fc receptor (FcRn) at a slightly acidic pH can protect IgG molecules from undergoing lysosomal or serum proteinase-induced degradation...
2018: Methods in Molecular Biology
E Sally Ward, Raimund J Ober
The MHC class I-related receptor FcRn serves multiple roles ranging from the regulation of levels of IgG isotype antibodies and albumin throughout the body to the delivery of antigen into antigen loading compartments in specialized antigen-presenting cells. In parallel with studies directed towards understanding FcRn at the molecular and cellular levels, there has been an enormous expansion in the development of engineering strategies involving FcRn to modulate the dynamic behavior of antibodies, antigens, and albumin...
October 2018: Trends in Pharmacological Sciences
Brian M Maas, Yanguang Cao
Manipulation of binding affinity between monoclonal antibodies (mAbs) and the neonatal Fc receptor (FcRn) has been leveraged to extend mAb half-life; however, the steps required for success remain ambiguous and experimental observations are inconsistent. Recent models have considered the time course of endosomal transit a major contributor to the relationship between FcRn affinity and antibody half-life. Our objective was to develop a minimal physiologically based pharmacokinetic model to explain how changes in IgG-FcRn association rate constant (Kon ), dissociation rate constant (Koff ), and endosomal transit time [T(w) ] translate to improved IgG clearance across mice, monkeys and humans...
August 21, 2018: MAbs
Bryan Smith, Andrea Kiessling, Rocio Lledo-Garcia, Kate L Dixon, Louis Christodoulou, Matthew C Catley, Paul Atherfold, Lena E D'Hooghe, Helene Finney, Kevin Greenslade, Hanna Hailu, Lara Kevorkian, Daniel Lightwood, Christoph Meier, Rebecca Munro, Omar Qureshi, Kaushik Sarkar, Sophie P Shaw, Roohi Tewari, Alison Turner, Kerry Tyson, Shauna West, Stevan Shaw, Frank R Brennan
Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin)...
October 2018: MAbs
Andreas Recke, Sarah Konitzer, Susanne Lemcke, Miriam Freitag, Nele Maxi Sommer, Mohammad Abdelhady, Mahsa M Amoli, Sandrine Benoit, Farha El-Chennawy, Mohammad Eldarouti, Rüdiger Eming, Regine Gläser, Claudia Günther, Eva Hadaschik, Bernhard Homey, Wolfgang Lieb, Wiebke K Peitsch, Claudia Pföhler, Reza M Robati, Marjan Saeedi, Miklós Sárdy, Michael Sticherling, Soner Uzun, Margitta Worm, Detlef Zillikens, Saleh Ibrahim, Gestur Vidarsson, Enno Schmidt
IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses...
2018: Frontiers in Immunology
Seungbin Cha, Sun Hwa Lee, Sung Hun Kang, Mohammad Nazmul Hasan, Young Jun Kim, Sungpil Cho, Yong-Kyu Lee
Background: Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-life (< 5 min) and rapid clearance of GLP-1 often limits its therapeutic use. Here, we developed an oral GLP-1 gene delivery system to achieve an extended antidiabetic effect. Methods: Human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared by an electrostatic complexation of the expression plasmid with various ratios of the positively modified Fc fragments of an antibody (hIgG1-Fc-Arg) having a targeting ability to FcRn receptor...
2018: Biomaterials Research
Simone Mader, Lior Brimberg, John N Soltys, Jeffrey L Bennett, Betty Diamond
Maternal antibodies provide protection for the developing fetus. Transplacental transport of pathogenic autoantibodies might pose a risk for the developing fetus. The transport of antibodies across the placenta to the fetal circulation occurs through the neonatal Fc salvage receptor (FcRn). During gestation, maternal autoantibodies are able to penetrate the embryonic brain before a functional intact blood-brain barrier is established. Brain-reactive antibodies to the water channel protein aquaporin-4 (AQP4) are a hallmark finding in neuromyelitis optica (NMO), a neurological disease that predominantly affects women, many of whom are of childbearing age...
2018: Frontiers in Immunology
Simone Ladel, Johannes Flamm, Arghavan Soleimani Zadeh, Dorothea Filzwieser, Julia-Christina Walter, Patrick Schlossbauer, Ralf Kinscherf, Katharina Lischka, Harald Luksch, Katharina Schindowski
BACKGROUND: The use of therapeutic antibodies for the treatment of neurological diseases is of increasing interest. Nose-to-brain drug delivery is one strategy to bypass the blood brain barrier. The neonatal Fc receptor (FcRn) plays an important role in transepithelial transcytosis of immunoglobulin G (IgG). Recently, the presence of the FcRn was observed in nasal respiratory mucosa. The aim of the present study was to determine the presence of functional FcRn in olfactory mucosa and to evaluate its role in drug delivery...
July 26, 2018: Pharmaceutics
Peter Ulrichts, Antonio Guglietta, Torsten Dreier, Tonke van Bragt, Valérie Hanssens, Erik Hofman, Bernhardt Vankerckhoven, Peter Verheesen, Nicolas Ongenae, Valentina Lykhopiy, F Javier Enriquez, JunHaeng Cho, Raimund J Ober, E Sally Ward, Hans de Haard, Nicolas Leupin
BACKGROUND: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs...
October 1, 2018: Journal of Clinical Investigation
Shan Chung, Yuwen Linda Lin, Van Nguyen, Lynn Kamen, Kai Zheng, Bianca Vora, An Song
The neonatal Fc receptor (FcRn) binds to the Fc domain of IgG in a pH-dependent manner, guides the intracellular movement of the bound antibodies and protects them from lysosomal degradation. Proper characterization of Fc-FcRn interactions is fundamental to successful design, development, and production of Fc-containing therapeutic proteins because of the potential impact of such interactions on their in vivo pharmacokinetic behaviors. Here, we describe the development and characterization of a cell-based, label-free FcRn-mediated transcytosis assay that provides a functional readout to reflect the totality of Fc-FcRn interactions, including pH-dependent association and dissociation, as well as the intracellular trafficking of Fc-containing molecules in complex with FcRn...
November 2018: Journal of Immunological Methods
Xiaoning Song, Rui Li, Hailiang Deng, Ye Li, Yanan Cui, Hua Zhang, Wenbing Dai, Bing He, Ying Zheng, Xueqing Wang, Qiang Zhang
Active-targeting nanocarriers can significantly improve the transcytosis of poorly water-soluble or bio-macromolecular drugs across biological barrier. However, reasons for the improvement are not understood enough, which hampered the reasonable design of active targeting nanocarriers. To illustrate how different factors influence the transport of active-targeting nanocarriers, we established ligand-decorated micelles targeting different receptors to study how the decorations influence the transcytosis of the micelles by comparing the endocytosis, transport pathway and exocytosis process...
October 2018: Biomaterials
Maja Thim Larsen, Helen Rawsthorne, Karen Kræmmer Schelde, Frederik Dagnæs-Hansen, Jason Cameron, Kenneth A Howard
Recombinant albumin-drug genetic fusions are an effective technology to prolong the serum half-life of therapeutics that has resulted in marketed products. Indirect evidence suggests albumin fusions' long circulation is controlled by engagement with the cellular recycling neonatal Fc receptor (FcRn) in addition to reduced kidney filtration. In this work, we have used a panel of recombinant fusions, engineered with different human FcRn (hFcRn) affinity, including a novel high binding albumin variant (HBII), to directly define and importantly, control the intracellular mechanism as a half-life extension tuning method...
October 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Deni Hardiansyah, Chee Meng Ng
The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population...
October 2018: MAbs
Mark A Bryniarski, Benjamin M Yee, Irum Jaffri, Lee D Chaves, Jin Ah Yu, Xiaowen Guan, Nazanin Ghavam, Rabi Yacoub, Marilyn E Morris
The megalin/cubilin complex is responsible for the majority of serum protein reclamation in the proximal tubules. The current study examined if decreases in their renal expression, along with the albumin recycling protein FcRn, could account for proteinuria/albuminuria in the Zucker Diabetic Fatty rat model of type 2 diabetic nephropathy. Immunoblots of renal cortex samples obtained at worsening disease stages demonstrated no loss in megalin, cubilin, or FcRn, even when proteinuria was measured. Additionally, early diabetic rats exhibited significantly increased renal megalin expression when compared to controls (adjusted p < 0...
June 27, 2018: American Journal of Physiology. Renal Physiology
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