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https://read.qxmd.com/read/30702442/platelet-derived-%C3%AE-2m-regulates-monocyte-inflammatory-responses
#1
Zachary T Hilt, Daphne N Pariser, Sara K Ture, Amy Mohan, Pearl Quijada, Akua Asante, Scott J Cameron, Julie A Sterling, Alyssa R Merkel, Andrew L Johanson, Jermaine L Jenkins, Eric M Small, Kathleen E McGrath, James Palis, Michael R Elliott, Craig N Morrell
Beta-2 microglobulin (β2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but β2M may also have less understood chaperoneindependent functions. Elevated plasma β2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. β2M mRNA is present in platelets at very high levels and β2M is part of the activated platelet releasate. In addition to their more well studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation...
January 31, 2019: JCI Insight
https://read.qxmd.com/read/30684504/intact-bioactivities-and-improved-pharmacokinetic-of-the-sl335-ifn-%C3%AE-1a-fusion-protein-that-created-by-genetic-fusion-of-sl335-a-human-anti-serum-albumin-fab-and-human-interferon-%C3%AE
#2
Soo-In Ji, Jeong-Ho Park, Hyo-Geun You, Hyun-Jin Chi, Ye-Won Bang, Sang-Hoon Cha
Recombinant human interferon beta (rIFN-β) has long been used as a first-line treatment for multiple sclerosis (MS), and any attempt to develop a long-acting rIFN-β is desirable since only one pegylated version of long-acting rIFN-β-1a (Plegridy) is currently available in clinics. Previously, we reported that SL335, a human Fab molecule specific to serum albumin, exhibits an extended serum half-life via utilizing the FcRn recycling mechanism. With the ultimate goal of developing a long-acting rIFN-®, we generated a fusion construct by linking human IFN-β cDNA to the C-terminus of the SL335 H chain at the DNA level followed by expression of the fusion protein, referred to as SL335-IFN-β-1a, in Chinese hamster ovary-S (CHO-S) cells...
January 23, 2019: Immunology Letters
https://read.qxmd.com/read/30683704/fc-sialylation-prolongs-serum-half-life-of-therapeutic-antibodies
#3
Mathilde Bas, Aurélie Terrier, Emilie Jacque, Aurélie Dehenne, Virginie Pochet-Béghin, Cécile Beghin, Anne-Sophie Dezetter, Gilles Dupont, Anaïs Engrand, Benjamin Beaufils, Philippe Mondon, Nathalie Fournier, Christophe de Romeuf, Sylvie Jorieux, Alexandre Fontayne, Lennart T Mars, Céline Monnet
The long serum t 1/2 of IgGs is ensured by their interaction with the neonatal Fc receptor (FcRn), which salvages IgG from intracellular degradation. Fc glycosylation is thought not to influence FcRn binding and IgG longevity in vivo. In this article, we demonstrate that hypersialylation of asparagine 297 (N297) enhances IgG serum persistence. This polarized glycosylation is achieved using a novel Fc mutation, a glutamate residue deletion at position 294 (Del) that endows IgGs with an up to 9-fold increase in serum lifespan...
January 25, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
https://read.qxmd.com/read/30653981/kras-enhanced-macropinocytosis-and-reduced-fcrn-mediated-recycling-sensitize-pancreatic-cancer-to-albumin-conjugated-drugs
#4
Huiqin Liu, Mengnan Sun, Zhengsheng Liu, Chao Kong, Weijian Kong, Junxiao Ye, Jianan Gong, David C S Huang, Feng Qian
Pancreatic ductal adenocarcinoma (PDAC) is a dominantly (~95%) KRAS-mutant cancer that has extremely poor prognosis, in part this is due to its strong intrinsic resistance towards almost all therapeutic agents. PDAC relies heavily on KRAS-transformed metabolism, including enhanced macropinocytosis and catabolism of extracellular albumin, to maintain its proliferation and progression. However, it has yet to be validated that whether such transformed metabolism could be exploited for the drug delivery to open therapeutic windows of cytotoxic agents in KRAS-mutant PDAC...
January 14, 2019: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://read.qxmd.com/read/30606013/site-specific-chemical-conjugation-of-antibodies-by-using-affinity-peptide-for-the-development-of-therapeutic-antibody-format
#5
Satoshi Kishimoto, Yuichi Nakashimada, Riri Yokota, Takaaki Hatanaka, Motoyasu Adachi, Yuji Ito
Artificially modified IgG molecules are increasingly utilized in industrial and clinical applications. In the present study, the method of chemical conjugation by affinity peptide (CCAP) for site-specific chemical modification has been developed by using a peptide that bound with high affinity to human IgG-Fc. This method enabled a rapid modification of a specific res-idue (Lys248 on Fc) in a one-step reaction under mild condition to form a stable amide bond between the peptide and Fc. The monovalent peptide-IgG conjugate not only maintained complete antigen binding but also bound to Fc receptors (FcRn, FcRγI, and FcRγIIIa), indicating that it is a suitable conjugate form that can be further developed into highly func-tional antibody therapeutics...
January 4, 2019: Bioconjugate Chemistry
https://read.qxmd.com/read/30604643/a-recycling-anti-transferrin-receptor-1-monoclonal-antibody-as-an-efficient-therapy-for-erythroleukemia-through-target-up-regulation-and-antibody-dependent-cytotoxic-effector-functions
#6
Madeline Neiveyans, Rana Melhem, Christophe Arnoult, Thomas Bourquard, Marta Jarlier, Muriel Busson, Adrien Laroche, Martine Cerutti, Martine Pugnières, David Ternant, Nadège Gaborit, Thierry Chardès, Anne Poupon, Valérie Gouilleux-Gruart, Andre Pèlegrin, Marie-Alix Poul
Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2 -Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2 -Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2 -Fc format...
January 3, 2019: MAbs
https://read.qxmd.com/read/30602565/a-new-class-of-recombinant-human-albumin-with-multiple-surface-thiols-exhibit-stable-conjugation-and-enhanced-fcrn-binding-and-blood-circulation
#7
Karen Kræmmer Schelde, Karl Nicholls, Frederik Dagnæs-Hansen, Karen Bunting, Helen Rawsthorne, Birgitte Andersen, Christopher J A Finnis, Miranda Williamson, Jason Cameron, Kenneth A Howard
Human serum albumin is an endogenous ligand transport protein whose long circulatory half-life is facilitated by engagement with the human cellular recycling neonatal Fc receptor (hFcRn). The single free thiol located at Cys-34 in domain I of albumin has been exploited for mono-conjugation of drugs. In this work, we increased the drug-to-albumin ratio potential by engineering recombinant human albumin (rHSA) variants with varying hFcRn affinity to contain three free, conjugation-competent cysteines. Structural analysis was used to identify positions for cysteine introduction to maximise rHSA stability and formation of the conjugated product without affecting hFcRn binding...
January 2, 2019: Journal of Biological Chemistry
https://read.qxmd.com/read/30600193/biosimilarity-assessment-of-biosimilar-therapeutic-monoclonal-antibodies
#8
REVIEW
Akiko Ishii-Watabe, Takashi Kuwabara
The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. During the development of a biosimilar, product quality should be evaluated and compared with those of the reference product extensively. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profile of the product...
December 7, 2018: Drug Metabolism and Pharmacokinetics
https://read.qxmd.com/read/30592762/antibody-engineering-to-generate-sky59-a-long-acting-anti-c5-recycling-antibody
#9
Zenjiro Sampei, Kenta Haraya, Tatsuhiko Tachibana, Taku Fukuzawa, Meiri Shida-Kawazoe, Siok Wan Gan, Yuichiro Shimizu, Yoshinao Ruike, Shu Feng, Taichi Kuramochi, Masaru Muraoka, Takehisa Kitazawa, Yoshiki Kawabe, Tomoyuki Igawa, Kunihiro Hattori, Junichi Nezu
Modulating the complement system is a promising strategy in drug discovery for disorders with uncontrolled complement activation. Although some of these disorders can be effectively treated with an antibody that inhibits complement C5, the high plasma concentration of C5 requires a huge dosage and frequent intravenous administration. Moreover, a conventional anti-C5 antibody can cause C5 to accumulate in plasma by reducing C5 clearance when C5 forms an immune complex (IC) with the antibody, which can be salvaged from endosomal vesicles by neonatal Fc receptor (FcRn)-mediated recycling...
2018: PloS One
https://read.qxmd.com/read/30529500/generation-of-two-high-affinity-anti-mouse-fcrn-antibodies-inhibition-of-igg-recycling-in-wild-type-mice-and-effect-in-a-mouse-model-of-immune-thrombocytopenia
#10
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...
January 2019: International Immunopharmacology
https://read.qxmd.com/read/30525379/microfluidic-nanoassembly-of-bioengineered-chitosan-modified-fcrn-targeted-porous-silicon-nanoparticles-hypromellose-acetate-succinate-for-oral-delivery-of-anti-diabetic-peptides
#11
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
https://read.qxmd.com/read/30471293/development-and-evaluation-of-a-physiologically-based-pharmacokinetic-model-for-predicting-the-effects-of-anti-fcrn-therapy-on-the-disposition-of-endogenous-igg-in-humans
#12
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
https://read.qxmd.com/read/30468828/the-potential-of-exosomes-from-cow-milk-for-oral-delivery
#13
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
https://read.qxmd.com/read/30466347/influence-of-n-glycosylation-on-effector-functions-and-thermal-stability-of-glycoengineered-igg1-monoclonal-antibody-with-homogeneous-glycoforms
#14
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
https://read.qxmd.com/read/30439342/cross-reactive-dengue-virus-antibodies-augment-zika-virus-infection-of-human-placental-macrophages
#15
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
https://read.qxmd.com/read/30423340/application-of-physiologically-based-pharmacokinetic-modeling-to-predict-the-effects-of-fcrn-inhibitors-in-mice-rats-and-monkeys
#16
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
https://read.qxmd.com/read/30402880/m281-an-anti-fcrn-antibody-pharmacodynamics-pharmacokinetics-and-safety-across-the-full-range-of-igg-reduction-in-a-first-in-human-study
#17
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
https://read.qxmd.com/read/30367290/fate-of-the-fc-fusion-protein-aflibercept-in-retinal-endothelial-cells-competition-of-recycling-and-degradation
#18
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
https://read.qxmd.com/read/30326650/fcrn-expression-in-wildtype-mice-transgenic-mice-and-in-human-tissues
#19
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
https://read.qxmd.com/read/30323819/lack-of-fcrn-impairs-natural-killer-cell-development-and-functions-in-the-tumor-microenvironment
#20
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
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