keyword
https://read.qxmd.com/read/38357917/an-engineered-immunomodulatory-igg1-fc-suppresses-autoimmune-inflammation-through-pathways-shared-with-i-v-immunoglobulin
#21
JOURNAL ARTICLE
Sunny L Sneed, Brian B Reese, Ana Fs Laureano, Sneha Ratnapriya, Isabella Fraschilla, Kate L Jeffrey, Greg P Coffey, Pamela B Conley, Robert M Anthony
Immunoglobulin G (IgG) antibodies in the form of high-dose intravenous immunoglobulin (IVIG) exert immunomodulatory activity and are used in this capacity to treat inflammatory and autoimmune diseases. Reductionist approaches have revealed that terminal sialylation of the single asparagine-linked (N-linked) glycan at position 297 of the IgG1 Fc bestows antiinflammatory activity, which can be recapitulated by introduction of an F241A point mutation in the IgG1 Fc (FcF241A). Here, we examined the antiinflammatory activity of CHO-K1 cell-produced FcF241A in vivo in models of autoimmune inflammation and found it to be independent of sialylation...
February 15, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38353127/albumin-influences-leucocyte-fcrn-expression-in-the-early-days-of-kidney-transplantation
#22
JOURNAL ARTICLE
Pierre Boulard, Nicolas Azzopardi, Romain Levard, Jean-Marie Cornec, Juliette Lamamy, Bérénice Prieur, Marie-Véronique Demattei, Hervé Watier, Philippe Gatault, Valérie Gouilleux-Gruart
FcRn, a receptor originally known for its involvement in IgG and albumin transcytosis and recycling, is also important in the establishment of the innate and adaptive immune response. Dysregulation of the immune response has been associated with variations in FcRn expression, as observed in cancer. Recently, a link between autophagy and FcRn expression has been demonstrated. Knowing that autophagy is strongly involved in the development of reperfusion injury in kidney transplantation and that albuminemia is transiently decreased in the first two weeks after transplantation, we investigated variations in FcRn expression after kidney transplantation...
February 13, 2024: Clinical and Experimental Immunology
https://read.qxmd.com/read/38352869/serum-immunoglobulin-or-albumin-binding-single-domain-antibodies-that-enable-tailored-half-life-extension-of-biologics-in-multiple-animal-species
#23
JOURNAL ARTICLE
Michiel M Harmsen, Bart Ackerschott, Hans de Smit
Single-domain antibody fragments (sdAbs) can be isolated from heavy-chain-only antibodies that occur in camelids or the heavy chain of conventional antibodies, that also occur in camelids. Therapeutic application of sdAbs is often complicated by their low serum half-life. Fusion to sdAb that bind to long-lived serum proteins albumin or IgG can prolong serum half-life of fusion partners. Such studies mostly focused on human application. For half-life prolongation in multiple animal species novel species cross-reacting sdAb are needed...
2024: Frontiers in Immunology
https://read.qxmd.com/read/38351566/-neonatal-fc-receptor-fcrn-a-novel-therapeutic-approach-for-autoimmune-disease
#24
JOURNAL ARTICLE
Hiroyuki Murai, Daisuke Harada
Neonatal Fc receptor (FcRn) is involved in recycling of IgG. Recycling begins with IgG-uptake into the cell through pinocytosis. Subsequently, IgG binds to FcRn in acidic vesicles, which results in the recycling of the FcRn-IgG complex to cell surface, and the release of IgG in blood with neutral pH. Whereas IgG unbound to FcRn is not recycled and thus degraded in lysosomes. Therefore, FcRn plays a critical role in maintaining IgG levels in the blood. Recently, FcRn has been considered a therapeutic target for autoimmune diseases caused by IgG autoantibodies, and FcRn inhibitors are developed as therapeutic agents for the diseases...
February 2024: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://read.qxmd.com/read/38350078/biological-evaluation-of-antibody-drug-conjugates-produced-by-tag-free-lipoate-ligase-a-modification
#25
JOURNAL ARTICLE
Shunsuke Yamazaki, Kenichiro Ito, Tsubasa Aoki, Naoko Arashida, Tomohiro Watanabe, Tomohiro Fujii, Yutaka Matsuda
The concept of tag-free protein modification has attracted considerable interest in chemical biology because of its flexible and straightforward reaction process. In 2021, a groundbreaking approach using lipoate ligase A (LplA) for tag-free enzymatic modification of antibodies was unveiled, demonstrating its potential for the generation of precise antibody conjugates. In this study, to further explore LplA-mediated antibody-drug conjugate (ADC) synthesis, we performed initial biological evaluations of ADCs synthesized using LplA...
February 13, 2024: Biochemistry
https://read.qxmd.com/read/38345213/cathepsin-b-processing-is-required-for-the-in-vivo-efficacy-of-albumin-drug-conjugates
#26
JOURNAL ARTICLE
Barbara Bernardim, João Conde, Tuuli Hakala, Julie B Becher, Mary Canzano, Aldrin V Vasco, Tuomas P J Knowles, Jason Cameron, Gonçalo J L Bernardes
Targeted drug delivery approaches that selectively and preferentially deliver therapeutic agents to specific tissues are of great interest for safer and more effective pharmaceutical treatments. We investigated whether cathepsin B cleavage of a valine-citrulline [VC( S )]-containing linker is required for the release of monomethyl auristatin E (MMAE) from albumin-drug conjugates. In this study, we used an engineered version of human serum albumin, Veltis High Binder II (HBII), which has enhanced binding to the neonatal Fc (fragment crystallizable) receptor (FcRn) to improve drug release upon binding and FcRn-mediated recycling...
February 12, 2024: Bioconjugate Chemistry
https://read.qxmd.com/read/38335568/translating-mechanisms-into-therapeutic-strategies-for-immune-thrombocytopenia-itp-lessons-from-clinical-trials
#27
REVIEW
Mahda Delshad, Zeinab Davoodi-Moghaddam, Atieh Pourbagheri-Sigaroodi, Mohammad Faranoush, Hassan Abolghasemi, Davood Bashash
Immune thrombocytopenia (ITP) is an autoimmune disorder that causes a significant reduction in peripheral blood platelet count. Fortunately, due to an increased understanding of ITP, there have been significant improvements in the diagnosis and treatment of these patients. Over the past decade, there have been a variety of proven therapeutic options available for ITP patients, including intravenous immunoglobulins (IVIG), Rituximab, corticosteroids, and thrombopoietin receptor agonists (TPO-RAs). Although the effectiveness of current therapies in treating more than two-thirds of patients, still some patients do not respond well to conventional therapies or fail to achieve long-term remission...
February 6, 2024: Thrombosis Research
https://read.qxmd.com/read/38334129/electrostatic-properties-of-human-germlines-and-biodistribution-of-small-biologics
#28
JOURNAL ARTICLE
Leticia Maria De Souza Cordeiro, Kelley Christine Atkinson, Argin Aivazian, Patrick Frank Joyce, Fang Jia, Alessandro Mascioni
Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver...
2024: MAbs
https://read.qxmd.com/read/38321574/generalized-myasthenia-gravis-with-acetylcholine-receptor-antibodies-a-guidance-for-treatment
#29
JOURNAL ARTICLE
Nils Erik Gilhus, Henning Andersen, Linda Kahr Andersen, Marion Boldingh, Sini Laakso, Margret Oddny Leopoldsdottir, Sidsel Madsen, Fredrik Piehl, Trine Haug Popperud, Anna Rostedt Punga, Liselotte Schirakow, John Vissing
BACKGROUND: Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. METHODS: MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings...
February 6, 2024: European Journal of Neurology
https://read.qxmd.com/read/38308492/how-should-newer-therapeutic-agents-be-incorporated-into-the-treatment-of-patients-with-myasthenia-gravis
#30
JOURNAL ARTICLE
Kelly G Gwathmey, Huanghe Ding, Michael Hehir, Nicholas Silvestri
Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials...
February 3, 2024: Muscle & Nerve
https://read.qxmd.com/read/38247105/chimerism-of-avian-igy-scfv-and-truncated-igg-fc-a-novel-strategy-in-cross-species-antibody-generation-and-enhancement
#31
JOURNAL ARTICLE
Shikun Ge, Alberto Carlos Pires Dias, Xiaoying Zhang
Chicken single-chain fragment variable (IgY-scFv) is a functional fragment and an emerging development in genetically engineered antibodies with a wide range of biomedical applications. However, scFvs have considerably shorter serum half-life due to the absence of antibody Fc region compared with the full-length antibody, and usually requires continuous intravenous administration for efficacy. A promising approach to overcome this limitation is to fuse scFv with immunoglobulin G (IgG) Fc region, for better recognition and mediation by the neonatal Fc receptor (FcRn) in the host...
January 21, 2024: Immunology
https://read.qxmd.com/read/38241085/interactions-of-the-anti-fcrn-monoclonal-antibody-rozanolixizumab-with-fc%C3%AE-receptors-and-functional-impact-on-immune-cells-in-vitro
#32
JOURNAL ARTICLE
Omar S Qureshi, Emma J Sutton, Rosemary F Bithell, Shauna M West, Rona M Cutler, Gillian McCluskey, Graham Craggs, Asher Maroof, Nicholas M Barnes, David P Humphreys, Stephen Rapecki, Bryan J Smith, Anthony Shock
Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly "silent" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab...
2024: MAbs
https://read.qxmd.com/read/38231391/an-albumin-holliday-junction-biomolecular-modular-design-for-programmable-multifunctionality-and-prolonged-circulation
#33
JOURNAL ARTICLE
Anders Dinesen, Veronica L Andersen, Marwa Elkhashab, Diego Pilati, Pernille Bech, Elisabeth Fuchs, Torbjørn R Samuelsen, Alexander Winther, Yunpeng Cai, Anders Märcher, Archie Wall, Marjan Omer, Jesper S Nielsen, Vijay Chudasama, James R Baker, Kurt V Gothelf, Jesper Wengel, Jørgen Kjems, Kenneth A Howard
Combinatorial properties such as long-circulation and site- and cell-specific engagement need to be built into the design of advanced drug delivery systems to maximize drug payload efficacy. This work introduces a four-stranded oligonucleotide Holliday Junction (HJ) motif bearing functional moieties covalently conjugated to recombinant human albumin (rHA) to give a "plug-and-play" rHA-HJ multifunctional biomolecular assembly with extended circulation. Electrophoretic gel-shift assays show successful functionalization and purity of the individual high-performance liquid chromatography-purified modules as well as efficient assembly of the rHA-HJ construct...
January 17, 2024: Bioconjugate Chemistry
https://read.qxmd.com/read/38215986/nanoparticles-targeting-the-intestinal-fc-receptor-enhance-intestinal-cellular-trafficking-of-semaglutide
#34
JOURNAL ARTICLE
Soraia Pinto, Mahya Hosseini, Stephen Buckley, Wen Yin, Javad Garousi, Torbjörn Gräslund, Sven van Ijzendoorn, Hélder A Santos, Bruno Sarmento
Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes. Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs...
January 10, 2024: Journal of Controlled Release
https://read.qxmd.com/read/38214218/a-modular-albumin-oligonucleotide-biomolecular-assembly-for-delivery-of-antisense-therapeutics
#35
JOURNAL ARTICLE
Marwa Elkhashab, Yeter Dilek, Morten Foss, Laura B Creemers, Kenneth A Howard
Antisense nucleic acid drugs are susceptible to nuclease degradation, rapid renal clearance, and short circulatory half-life. In this work, we introduce a modular-based recombinant human albumin-oligonucleotide (rHA-cODN) biomolecular assembly that allows incorporation of a chemically stabilized therapeutic gapmer antisense oligonucleotide (ASO) and FcRn-driven endothelial cellular recycling. A phosphodiester ODN linker (cODN) was conjugated to recombinant human albumin (rHA) using maleimide chemistry, after which a complementary gapmer ASO, targeting ADAMTS5 involved in osteoarthritis pathogenesis, was annealed...
January 12, 2024: Molecular Pharmaceutics
https://read.qxmd.com/read/38212881/does-anti-hpa-1a-affect-birthweight-in-fetal-and-neonatal-alloimmune-thrombocytopenia
#36
JOURNAL ARTICLE
Margaret McKelvy, Srishti Tyagi, Emilie Vander Haar, Madhavi Lakkaraja, Tim Tomy, Stacy Corke, Thea Palmer, Amihai Rottenstreich, Rick Kapur, Huiying Zhi, Debra Newman, Nina Scatz-Siemers, James Bussel
BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) ensues from parental incompatibility for platelet alloantigens with maternal sensitization. HPA-1a/1b incompatibility is the most common cause of FNAIT in Caucasians. Placental villitis and lower birthweight in FNAIT suggest anti-HPA-1a may have effects beyond inducing thrombocytopenia. OBJECTIVES: Does FNAIT secondary to anti-HPA-1a result in smaller newborns and, the corollary, does antenatal management of FNAIT increase birthweight? STUDY DESIGN: Birthweights of 270 FNAIT-affected newborns from a randomized clinical trial and a NAITbabies...
January 11, 2024: Pediatric Blood & Cancer
https://read.qxmd.com/read/38205888/association-of-the-neonatal-fc-receptor-promoter-variable-number-of-tandem-repeat-polymorphism-with-immunoglobulin-response-in-patients-with-chronic-inflammatory-demyelinating-polyneuropathy
#37
JOURNAL ARTICLE
Anna Lena Fisse, Emelie Schäfer, Alina Hieke, Maximilian Schröder, Rafael Klimas, Jil Brünger, Sophie Huckemann, Thomas Grüter, Melissa Sgodzai, Christiane Schneider-Gold, Ralf Gold, Huu Phuc Nguyen, Kalliopi Pitarokoili, Jeremias Motte, Larissa Arning
BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein...
January 11, 2024: European Journal of Neurology
https://read.qxmd.com/read/38164996/efgartigimod-in-generalized-myasthenia-gravis-a-real-life-experience-at-a-national-reference-center
#38
JOURNAL ARTICLE
Rita Frangiamore, Elena Rinaldi, Fiammetta Vanoli, Francesca Andreetta, Emilio Ciusani, Silvia Bonanno, Lorenzo Maggi, Annamaria Gallone, Anna Colasuonno, Irene Tramacere, Marta Cheli, Alessandro Pinna, Renato Mantegazza, Carlo Antozzi
BACKGROUND AND PURPOSE: Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. METHODS: EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening)...
January 2, 2024: European Journal of Neurology
https://read.qxmd.com/read/38145833/decoupling-fcrn-and-tumor-contributions-to-elevated-immune-checkpoint-inhibitor-clearance-in-cancer-cachexia
#39
JOURNAL ARTICLE
Trang T Vu, Kyeongmin Kim, Millennium Manna, Justin Thomas, Bryan Remaily, Emma J Montgomery, Travis Costa, Lauren Granchie, Zhiliang Xie, Yizhen Guo, Min Chen, Alyssa Marie M Castillo, Samuel K Kulp, Xiaokui Mo, Sridhar Nimmagadda, Paul Gregorevic, Dwight H Owen, Latha P Ganesan, Thomas A Mace, Christopher C Coss, Mitch A Phelps
High baseline clearance of immune checkpoint inhibitors (ICIs), independent of dose or systemic exposure, is associated with cachexia and poor outcomes in cancer patients. Mechanisms linking ICI clearance, cachexia and ICI therapy failure are unknown. Here, we evaluate in four murine models and across multiple antibodies whether altered baseline catabolic clearance of administered antibody requires a tumor and/or cachexia and whether medical reversal of cachexia phenotype can alleviate altered clearance. Key findings include mild cachexia phenotype and lack of elevated pembrolizumab clearance in the MC38 tumor-bearing model...
December 23, 2023: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://read.qxmd.com/read/38140161/delving-into-molecular-pathways-analyzing-the-mechanisms-of-action-of-monoclonal-antibodies-integrated-in-imgt-mab-db-for-myasthenia-gravis
#40
REVIEW
Rebecca Golfinopoulou, Véronique Giudicelli, Taciana Manso, Sofia Kossida
BACKGROUND: Myasthenia Gravis (MG) is a rare autoimmune disease presenting with auto-antibodies that affect the neuromuscular junction. In addition to symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT® , the international ImMunoGeneTics information system® , extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB...
November 26, 2023: Vaccines
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