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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 immunoglobulin (IVIg), plasma exchange and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches to modulate IgG levels can however be associated with some severe adverse reactions and significant burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and convenient alternative for clearing pathogenic IgGs...
July 24, 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...
July 18, 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...
July 14, 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...
July 3, 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
Brian J Booth, Boopathy Ramakrishnan, Kristin Narayan, Andrew M Wollacott, Gregory J Babcock, Zachary Shriver, Karthik Viswanathan
Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously...
June 27, 2018: MAbs
Kelly D Moynihan, Rebecca L Holden, Naveen K Mehta, Chensu Wang, Mark R Karver, Jens Dinter, Simon Liang, Wuhbet Abraham, Mariane B Melo, Angela Q Zhang, Na Li, Sylvie Le Gall, Bradley Pentelute, Darrell J Irvine
Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses...
June 18, 2018: Cancer Immunology Research
Chenxu Zhao, Ying Gao, Nan Yu, Tiancheng Li, Yang Zhang, Hong Zhang, Guizhi Lu, Yanming Gao, Xiaohui Guo
Neonatal Fc receptor (FcRn) is down-regulated in Hashimoto's thyroiditis (HT) thyrocytes and mediates IgG endocytosis in thyrocytes. The serum distribution of IgG subclasses (of TgAb and TPOAb) differs between HT patients and normal individuals. We aimed to explore the direction and regulation of FcRn-mediated IgG transport in thyrocyte monolayers and the difference between various IgG subclass transport. IgG was transported by FcRn from the basolateral to apical side in the thyrocyte monolayers grown on Transwell filters and the transport was inhibited by IFN-γ and TNF-α...
June 14, 2018: Molecular and Cellular Endocrinology
Byungseop Yang, Jong Chul Kim, Jihyoun Seong, Giyoong Tae, Inchan Kwon
Human serum albumin (HSA) has been investigated as a serum half-life extender of therapeutic proteins thanks to its unusually long serum half-life. However, in mice, the serum half-life of a HSA-conjugated protein was much shorter than that of HSA in humans, likely due to the species-dependent nature of albumin-FcRn interactions. Herein, we investigated species-dependent albumin-FcRn interactions using species-matched albumin (mouse serum albumin) and species-mismatched albumin (HSA) in non-transgenic mice...
July 24, 2018: Biomaterials Science
Amita Datta-Mannan, Jeffrey Boyles, Lihua Huang, Zhaoyan Y Jin, Amber Peariso, Anthony T Murphy, Bernice Ellis, Nicole Douglass, Fariba Norouziyan-Cooper, Derrick R Witcher
There is a rapidly growing reinvigoration of the investigation of small proteins, cyclic peptides, and mAb derived domains as biotherapies. The drugability of these structures are challenged by fast peripheral clearance properties that can reduce their potential to be realized as medicines. Engineering strategies have been of limited value because mechanistically the half-life benefit is manifested by increasing the molecular weight and/or the hydrodyanimc radius which slows the molecule's renal elimination, but can result in the inherent loss of activity and target accessibility...
May 26, 2018: Biotechnology Journal
Ingrid J G Burvenich, William Farrugia, Zhanqi Liu, Dahna Makris, Dylan King, Benjamin Gloria, Angelo Perani, Laura C Allan, Andrew M Scott, Paul A Ramsland
Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of fragment crystallizable (Fc) mutations targeting the neonatal Fc receptor (FcRn) site on a Lewis Y (Ley ) binding IgG1, hu3S193. The hu3S193 variants displayed shortened in vivo half-lives and may have potential for radioimaging or radiotherapy of Ley -positive tumors. Here, we report Fc crystal structures of wild-type hu3S193, seven FcRn-binding site variants, and a variant lacking C1q binding or complement-dependent cytotoxicity (CDC) activity...
July 5, 2018: Biochemical Journal
Ning Li, Donna Culton, Luis A Diaz, Zhi Liu
Bullous pemphigoid is an autoantibody-mediated skin blistering disease. Previous studies revealed that intravenous Ig is therapeutic in animal models of bullous pemphigoid by saturating the IgG-protective receptor FcRn, thereby accelerating degradation of pathogenic IgG. Sasaoka et al. demonstrate that the inhibitory effects of intravenous Ig on bullous pemphigoid are also associated with negative modulation of cytokine production by keratinocytes.
June 2018: Journal of Investigative Dermatology
Daniel Stöppler, Alex Macpherson, Susanne Smith-Penzel, Nicolas Basse, Fabien Lecomte, Hervé Deboves, Richard D Taylor, Tim Norman, John Porter, Lorna C Waters, Marta Westwood, Ben Cossins, Katharine Cain, James White, Robert Griffin, Christine Prosser, Sebastian Kelm, Amy H Sullivan, David Fox, Mark D Carr, Alistair Henry, Richard Taylor, Beat H Meier, Hartmut Oschkinat, Alastair D Lawson
Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG...
May 2018: PLoS Biology
Natalia A Lozano, Alejandro Lozano, Vanina Marini, Ricardo J Saranz, Richard S Blumberg, Kristi Baker, Maria F Agresta, Marina F Ponzio
PROBLEM: IgG is the only antibody class, that is, actively transferred from the mother to the fetus across the placenta by an active, neonatal Fc receptor (FcRn) mediated process during pregnancy, conferring passive immunity and protection against infections to the newborn during the first months of life. Preterm infants may not receive sufficient titers of protective antibodies, as most of them are transferred only after the 34th week of gestation. Because of the great importance of this process, we investigated in a clinical setting the placental transmission of IgG antibodies in term and preterm newborns...
May 10, 2018: American Journal of Reproductive Immunology: AJRI
Joshua W Wang, Wai Hong Wu, Tsui-Chin Huang, Margaret Wong, Kihyuck Kwak, Keiko Ozato, Chien-Fu Hung, Richard B S Roden
To address how L2-specific antibodies prevent human papillomavirus (HPV) infection of the genital tract, we generated neutralizing monoclonal antibodies (MAbs) WW1, a rat IgG2a that binds L2 residues 17 to 36 (like mouse MAb RG1), and JWW3, a mouse IgG2b derivative of Mab24 specific for L2 residues 58 to 64. By Western blotting, WW1 recognized L2 of 29/34 HPV genotypes tested, compared to only 13/34 for RG1 and 25/34 for JWW3. WW1 IgG and F(ab')2 bound HPV16 pseudovirions similarly; however, whole IgG provided better protection against HPV vaginal challenge...
August 1, 2018: Journal of Virology
Frank A Engler, Joseph Ryan Polli, Tommy Li, Bo An, Michael Otteneder, Jun Qu, Joseph P Balthasar
In this study, we examined the effects of target expression, neonatal Fc receptor (FcRn) expression in tumors, and pH-dependent target binding on the disposition of monoclonal antibodies (mAbs) in murine models of colorectal cancer. A panel of anti-carcinoembryonic antigen (CEA) mAbs was developed via standard hybridoma technology and then evaluated for pH-dependent CEA binding. Binding was assessed via immunoassay and radioligand binding assays. 10H6, a murine IgG1 mAb with high affinity for CEA at pH = 7...
July 2018: Journal of Pharmacology and Experimental Therapeutics
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