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Bryan Smith, Louis Christodoulou, Alison Clargo, Alison Eddleston, Kevin Greenslade, Daniel Lightwood, Anthony Shock, Kerry Tyson, Frank R Brennan
Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by pathogenic immunoglobulin G (IgG) autoantibodies that bind to platelets, causing their phagocytic removal and leading to reductions in platelet number. The neonatal Fc receptor (FcRn) selectively salvages and recycles IgG, including pathogenic IgG, thereby extending the half-life of IgG in plasma. Two anti-mouse FcRn monoclonal antibodies (mAb) (4470 and 4464) were generated to evaluate the effect of inhibiting IgG recycling. Statistically significant reductions in plasma IgG concentration were observed upon administration of 4470 (10, 30 and 100 mg/kg) in wild-type mice...
December 4, 2018: International Immunopharmacology
João Martins, Dongfei Liu, Flavia Fontana, Mónica Ferreira, Alexandra Correia, Silvia Valentino, Marianna Kemell, Karina Moslova, Ermei M Mäkilä, Jarno J Salonen, Jouni Hirvonen, Bruno Sarmento, Hélder A Santos
Microfluidics technology is emerging as a promising strategy to improve the oral delivery of proteins and peptides. Herein, a multistage drug delivery system is proposed as a step forward in the development of non-invasive therapies. Undecylenic acid modified thermally hydrocarbonized porous silicon (UnPSi) nanoparticles (NPs) were functionalized with the Fc fragment of immunoglobulin G for targeting purposes. Glucagon like peptide-1 (GLP-1) was loaded into the NPs as a model anti-diabetic drug. Fc-UnPSi NPs were coated with mucoadhesive chitosan, and ultimately entrapped into a polymeric matrix with pH-responsive properties by microfluidic nanoprecipitation...
December 7, 2018: ACS Applied Materials & Interfaces
Tommy Li, Joseph P Balthasar
This work scaled up a previously developed physiologically-based pharmacokinetic (PBPK) model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single and multiple-dose administration of anti-FcRn monoclonal antibodies (anti-FcRn mAb, 1 - 256 mg/kg) and high dose intravenous immune globulin (IVIG, 0.4 - 2 g/kg). The model was evaluated for prediction accuracy through comparison to the effects of rozanolixizumab, an anti-FcRn mAb under current clinical evaluation, on the disposition of endogenous IgG in healthy human subjects...
November 21, 2018: Journal of Pharmaceutical Sciences
Jamie L Betker, Brittany M Angle, Michael W Graner, Thomas J Anchordoquy
Many pharmaceuticals must be administered intravenously due to their poor oral bioavailability. In addition to issues associated with sterility and inconvenience, the cost of repeated infusion over a six-week course of therapy costs the healthcare system tens of billions of dollars per year. Attempts to improve oral bioavailability have traditionally focused on enhancing drug solubility and membrane permeability, and the use of synthetic nanoparticles has also been investigated. As an alternative strategy, some recent reports have clearly demonstrated that exosomes from cow milk are absorbed from the gastrointestinal tract in humans, and could potentially be used for oral delivery of drugs that are traditionally administered intravenously...
November 20, 2018: Journal of Pharmaceutical Sciences
Ryuta Wada, Makoto Matsui, Nana Kawasaki
Glycosylation of the conserved asparagine residue in each heavy chain of IgG in the CH2 domain is known as N-glycosylation. It is one of the most common post-translational modifications and important critical quality attributes of monoclonal antibody (mAb) therapeutics. Various studies have demonstrated the effects of the Fc N-glycosylation on safety, Fc effector functions, and pharmacokinetics, both dependent and independent of neonatal Fc receptor (FcRn) pathway. However, separation of various glycoforms to investigate the biological and functional relevance of glycosylation is a major challenge, and existing studies often discuss the overall impact of N-glycans, without considering the individual contributions of each glycoform when evaluating mAbs with highly heterogeneous distributions...
November 22, 2018: MAbs
Matthew G Zimmerman, Kendra M Quicke, Justin T O'Neal, Nitin Arora, Deepa Machiah, Lalita Priyamvada, Robert C Kauffman, Emery Register, Oluwaseyi Adekunle, Dominika Swieboda, Erica L Johnson, Sarah Cordes, Lisa Haddad, Rana Chakraborty, Carolyn B Coyne, Jens Wrammert, Mehul S Suthar
Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses...
November 14, 2018: Cell Host & Microbe
Tommy Li, Joseph P Balthasar
There is a growing interest in developing inhibitors of the neonatal Fc-receptor, FcRn, for use in the treatment for humoral autoimmune conditions. We have developed a new physiological based pharmacokinetic (PBPK) model that is capable of characterizing the pharmacokinetics and pharmacodynamics (PK/PD) of anti-FcRn monoclonal antibodies (mAb) in mice, rats, and monkeys. The model includes incorporation of FcRn recycling of immune gamma globulin (IgG) in hematopoietic cells in addition to FcRn recycling of IgG in vascular endothelial cells, and considers FcRn turnover and intracellular cycling...
November 10, 2018: Journal of Pharmaceutical Sciences
Leona Ling, Jan L Hillson, Renger G Tiessen, Tjerk Bosje, Mattheus Paulus van Iersel, Darrell J Nix, Lynn Markowitz, Nicholas A Cilfone, Jay Duffner, Jim Streisand, Anthony M Manning, Santiago Arroyo
M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses...
November 6, 2018: Clinical Pharmacology and Therapeutics
Heidrun L Deissler, Gerhard K Lang, Gabriele E Lang
PURPOSE: Intravitreal injection of the VEGF-binding protein aflibercept is widely used to treat various ocular diseases. In vitro, immortalized bovine retinal endothelial cells (iBREC) take up and transport aflibercept through the cell layer in a serum-dependent manner, likely mediated through the neonatal Fc receptor (FcRn), but degradation of the Fc domain-containing protein might be a competing intracellular process. Therefore, aflibercept's associations with proteins either involved in FcRn-mediated transport or in the lysosomal pathway were studied...
October 26, 2018: Graefe's Archive for Clinical and Experimental Ophthalmology
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...
December 1, 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 an 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 biologic or biophysical mechanisms must be accounted for. mAb thermal stability, which reflects its unfolding and aggregation propensities, may also relate to its pharmacokinetic properties...
December 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
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