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https://www.readbyqxmd.com/read/29771629/brain-uptake-of-multivalent-and-multi-specific-dvd-ig-proteins-after-systemic-administration
#1
Denise Karaoglu Hanzatian, Annette Schwartz, Farid Gizatullin, Jamie Erickson, Kangwen Deng, Ruth Villanueva, Christopher Stedman, Cristina Harris, Tariq Ghayur, Andrew Goodearl
Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would...
May 17, 2018: MAbs
https://www.readbyqxmd.com/read/29757698/prediction-of-non-linear-pharmacokinetics-in-humans-of-an-antibody-drug-conjugate-adc-when-evaluation-of-higher-doses-in-animals-is-limited-by-tolerability-case-study-with-an-anti-cd33-adc
#2
Isabel Figueroa, Doug Leipold, Steve Leong, Bing Zheng, Montserrat Carrasco-Triguero, Aimee Fourie-O'Donohue, Katherine R Kozak, Keyang Xu, Melissa Schutten, Hong Wang, Andrew G Polson, Amrita V Kamath
For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design...
May 14, 2018: MAbs
https://www.readbyqxmd.com/read/29733750/delivery-of-alx-0171-by-inhalation-greatly-reduces-respiratory-syncytial-virus-disease-in-newborn-lambs
#3
Alejandro Larios Mora, Laurent Detalle, Jack M Gallup, Albert Van Geelen, Thomas Stohr, Linde Duprez, Mark R Ackermann
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory disease in infants and young children worldwide. Currently, treatment is supportive and no vaccines are available. The use of newborn lambs to model hRSV infection in human infants may provide a valuable tool to assess safety and efficacy of new antiviral drugs and vaccines. ALX-0171 is a trivalent Nanobody targeting the hRSV fusion (F) protein and its therapeutic potential was evaluated in newborn lambs infected with a human strain of RSV followed by daily ALX-0171 nebulization for 3 or 5 consecutive days...
May 7, 2018: MAbs
https://www.readbyqxmd.com/read/29733746/the-less-is-more-in-therapeutic-antibodies-afucosylated-anti-cancer-antibodies-with-enhanced-antibody-dependent-cellular-cytotoxicity
#4
Natasha A Pereira, Kah Fai Chan, Pao Chun Lin, Zhiwei Song
Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity...
May 7, 2018: MAbs
https://www.readbyqxmd.com/read/29708852/fab-is-the-most-efficient-format-to-express-functional-antibodies-by-yeast-surface-display
#5
Coline Sivelle, Raphaël Sierocki, Kelly Ferreira-Pinto, Stéphanie Simon, Bernard Maillere, Hervé Nozach
Multiple formats are available for engineering of monoclonal antibodies (mAbs) by yeast surface display, but they do not all lead to efficient expression of functional molecules. We therefore expressed four anti-tumor necrosis factor and two anti-IpaD mAbs as single-chain variable fragment (scFv), antigen-binding fragment (Fab) or single-chain Fabs and compared their expression levels and antigen-binding efficiency. Although the scFv and scFab formats are widely used in the literature, 2 of 6 antibodies were either not or weakly expressed...
April 30, 2018: MAbs
https://www.readbyqxmd.com/read/29658818/a-long-non-coding-sineup-rna-boosts-semi-stable-production-of-fully-human-monoclonal-antibodies-in-hek293e-cells
#6
Emanuele Sasso, Debora Latino, Guendalina Froechlich, Mariangela Succoio, Margherita Passariello, Claudia De Lorenzo, Alfredo Nicosia, Nicola Zambrano
Use of monoclonal antibodies is emerging as a highly promising and fast-developing scenario for innovative treatment of viral, autoimmune and tumour diseases. The search for diagnostic and therapeutic antibodies currently depends on in vitro screening approaches, such as phage and yeast display technologies. Antibody production still represents a critical step for preclinical and clinical evaluations. Accordingly, improving production of monoclonal antibodies represents an opportunity, to facilitate downstream target validations...
April 16, 2018: MAbs
https://www.readbyqxmd.com/read/29652547/n-terminal-%C3%AE-amino-group-modification-of-antibodies-using-a-site-selective-click-chemistry-method
#7
De-Zhi Li, Bing-Nan Han, Rui Wei, Gui-Yang Yao, Zhizhen Chen, Jie Liu, Terence C W Poon, Wu Su, Zhongyu Zhu, Dimiter S Dimitrov, Qi Zhao
Site-specific conjugation of small molecules to antibody molecules is a promising strategy for generation of antibody-drug conjugates. In this report, we describe the successful synthesis of a novel bifunctional molecule, 6-(azidomethyl)-2-pyridinecarboxyaldehyde (6-AM-2-PCA), which was used for conjugation of small molecules to peptides and antibodies. We demonstrated that 6-AM-2-PCA selectively reacted with N-terminal amino groups of peptides and antibodies. In addition, the azide group of 6-AM-2-PCA enabled copper-free click chemistry coupling with dibenzocyclooctyne-containing reagents...
April 13, 2018: MAbs
https://www.readbyqxmd.com/read/29648920/functional-domain-analysis-of-sox18-transcription-factor-using-a-single-chain-variable-fragment-based-approach
#8
Frank R Fontaine, Stephen Goodall, Jeremy W Prokop, Christopher B Howard, Mehdi Moustaqil, Somuah Kumble, Daniel T Rasicci, Geoffrey W Osborne, Yann Gambin, Emma Sierecki, Martina L Jones, Johannes Zuegg, Stephen Mahler, Mathias Francois
Antibodies are routinely used to study the activity of transcription factors, using various in vitro and in vivo approaches such as electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, genome-wide method analysis coupled with next generation sequencing, or mass spectrometry. More recently, a new application for antibodies has emerged as crystallisation scaffolds for difficult to crystallise proteins, such as transcription factors. Only in a few rare cases, antibodies have been used to modulate the activity of transcription factors, and there is a real gap in our knowledge on how to efficiently design antibodies to interfere with transcription...
April 12, 2018: MAbs
https://www.readbyqxmd.com/read/29634430/linear-pharmacokinetic-parameters-for-monoclonal-antibodies-are-similar-within-a-species-and-across-different-pharmacological-targets-a-comparison-between-human-cynomolgus-monkey-and-hfcrn-tg32-transgenic-mouse-using-a-population-modeling-approach
#9
Alison Betts, Anne Keunecke, Tamara J van Steeg, Piet H van der Graaf, Lindsay B Avery, Hannah Jones, Jan Berkhout
The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs...
April 10, 2018: MAbs
https://www.readbyqxmd.com/read/29621428/hematopoietic-cells-as-site-of-first-pass-catabolism-after-subcutaneous-dosing-and-contributors-to-systemic-clearance-of-a-monoclonal-antibody-in-mice
#10
Wolfgang F Richter, Gregory J Christianson, Nicolas Frances, Hans Peter Grimm, Gabriele Proetzel, Derry C Roopenian
The neonatal Fc receptor (FcRn) has been demonstrated to contribute to a high bioavailability of monoclonal antibodies (mAbs). In this study, we explored the cellular sites of FcRn-mediated protection after subcutaneous (SC) and intravenous (IV) administration. SC absorption and IV disposition kinetics of a mAb were studied in hFcRn transgenic (Tg) bone marrow chimeric mice in which hFcRn was restricted to radioresistant cells or hematopoietic cells. SC bioavailabilities close to 90% were observed in hFcRn Tg mice and chimeric mice with hFcRn expression in hematopoietic cells, whereas SC bioavailabilities were markedly lower when FcRn was missing in hematopoietic cells...
April 5, 2018: MAbs
https://www.readbyqxmd.com/read/29595369/corrigendum
#11
(no author information available yet)
No abstract text is available yet for this article.
March 29, 2018: MAbs
https://www.readbyqxmd.com/read/29589989/a-unique-allosteric-insulin-receptor-monoclonal-antibody-that-prevents-hypoglycemia-in-the-sur-1-mouse-model-of-katp-hyperinsulinism
#12
Puja Patela, Lawrenshey Charles, John Corbin, Ira D Goldfine, Kirk Johnson, Paul Rubin, Diva D De León
Loss-of-function mutations of the ß-cell ATP-sensitive potassium channels (KATP ) cause the most common and severe form of congenital hyperinsulinism (KATP HI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KATP HI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in KATP HI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of KATP HI (SUR-1- / - mice)...
March 28, 2018: MAbs
https://www.readbyqxmd.com/read/29553870/improved-in-vitro-and-in-vivo-activity-against-cd303-expressing-targets-of-the-chimeric-122a2-antibody-selected-for-specific-glycosylation-pattern
#13
Nathalie Fournier, Emilie Jacque, Alexandre Fontayne, Delphine Derache, Gilles Dupont, Lucie Verhaeghe, Linda Baptista, Aurélie Dehenne, Anne-Sophie Dezetter, Aurélie Terrier, Alain Longue, Virginie Pochet-Beghin, Cecile Beghin, Sami Chtourou, Christophe de Romeuf
Plasmacytoid dendritic cells (pDCs) play a central role for both innate and adaptive antiviral responses, as they direct immune responses through their unique ability to produce substantial concentrations of type I interferon (IFNs) upon viral encounter while also activating multiple immune cells, including macrophages, DCs, B, natural killer and T cells. Recent evidence clearly indicates that pDCs also play a crucial role in some cancers and several auto-immune diseases. Although treatments are currently available to patients with such pathologies, many are not fully efficient...
March 19, 2018: MAbs
https://www.readbyqxmd.com/read/29553864/analytical-and-functional-similarity-of-amgen-biosimilar-abp-215-to-bevacizumab
#14
Neungseon Seo, Alla Polozova, Mingxuan Zhang, Zachary Yates, Shawn Cao, Huimin Li, Scott Kuhns, Gwendolyn Maher, Helen J McBride, Jennifer Liu
ABP 215 is a biosimilar product to bevacizumab. Bevacizumab acts by binding to vascular endothelial growth factor A, inhibiting endothelial cell proliferation and new blood vessel formation, thereby leading to tumor vasculature normalization. The ABP 215 analytical similarity assessment was designed to assess the structural and functional similarity of ABP 215 and bevacizumab sourced from both the United States (US) and the European Union (EU). Similarity assessment was also made between the US- and EU-sourced bevacizumab to assess the similarity between the two products...
March 19, 2018: MAbs
https://www.readbyqxmd.com/read/29553863/reformatting-palivizumab-and-motavizumab-from-igg-to-human-iga-impairs-their-efficacy-against-rsv-infection-in-vitro-and-in-vivo
#15
Shamir R Jacobino, Maaike Nederend, J Frederiek Reijneveld, Daan Augustijn, J H Marco Jansen, Jan Meeldijk, Karli R Reiding, Manfred Wuhrer, Frank E J Coenjaerts, C Erik Hack, Louis J Bont, Jeanette H W Leusen
Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization and mortality in young children. Protective therapy options are limited. Currently, palivizumab, a monoclonal IgG1 antibody, is the only licensed drug for RSV prophylaxis, although other IgG antibody candidates are being evaluated. However, at the respiratory mucosa, IgA antibodies are most abundant and act as the first line of defense against invading pathogens. Therefore, it would be logical to explore the potential of recombinant human IgA antibodies to protect against viral respiratory infection, but very little research on the topic has been published...
March 19, 2018: MAbs
https://www.readbyqxmd.com/read/29537925/modification-of-the-kinetic-stability-of-immunoglobulin-g-by-solvent-additives
#16
Jonas V Schaefer, Erik Sedlák, Florian Kast, Michal Nemergut, Andreas Plückthun
Biophysical properties of antibody-based biopharmaceuticals are a critical part of their release criteria. In this context, finding the appropriate formulation is equally important as optimizing their intrinsic biophysical properties through protein engineering, and both are mutually dependent. Most previous studies have empirically tested the impact of additives on measures of colloidal stability, while mechanistic aspects have usually been limited to only the thermodynamic stability of the protein. Here we emphasize the kinetic impact of additives on the irreversible denaturation steps of immunoglobulins G (IgG) and their antigen-binding fragments (Fabs), as these are the key committed steps preceding aggregation, and thus especially informative in elucidating the molecular parameters of activity loss...
March 14, 2018: MAbs
https://www.readbyqxmd.com/read/29513619/analytical-comparability-study-of-recombinant-monoclonal-antibody-therapeutics
#17
Alexandre Ambrogelly, Stephen Gozo, Amit Katiyar, Shara Dellatore, Yune Kune, Ram Bhat, Joanne Sun, Ning Li, Dongdong Wang, Christine Nowak, Alyssa Neill, Gomathinayagam Ponniah, Cory King, Bruce Mason, Alain Beck, Hongcheng Liu
Process changes are inevitable in the life cycle of recombinant monoclonal antibody therapeutics. Products made using pre- and post-change processes are required to be comparable as demonstrated by comparability studies to qualify for continuous development and commercial supply. Establishment of comparability is a systematic process of gathering and evaluating data based on scientific understanding and clinical experience of the relationship between product quality attributes and their impact on safety and efficacy...
March 7, 2018: MAbs
https://www.readbyqxmd.com/read/29494279/a-multiplatform-strategy-for-the-discovery-of-conventional-monoclonal-antibodies-that-inhibit-the-voltage-gated-potassium-channel-kv1-3
#18
Janna Bednenko, Rian Harriman, Lore Mariën, Hai M Nguyen, Alka Agrawal, Ashot Papoyan, Yelena Bisharyan, Joanna Cardarelli, Donna Cassidy-Hanley, Ted Clark, Darlene Pedersen, Yasmina Abdiche, William Harriman, Bas van der Woning, Hans de Haard, Ellen Collarini, Heike Wulff, Paul Colussi
Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein...
March 1, 2018: MAbs
https://www.readbyqxmd.com/read/29494273/automated-high-throughput-microscale-antibody-purification-workflows-for-accelerating-antibody-discovery
#19
Peng Luan, Sophia Lee, Tia A Arena, Maciej Paluch, Joe Kansopon, Sharon Viajar, Zahira Begum, Nancy Chiang, Gerald Nakamura, Philip E Hass, Athena W Wong, Greg A Lazar, Avinash Gill
To rapidly find "best-in-class" antibody therapeutics, it has become essential to develop high throughput (HTP) processes that allow rapid assessment of antibodies for functional and molecular properties. Consequently, it is critical to have access to sufficient amounts of high quality antibody, to carry out accurate and quantitative characterization. We have developed automated workflows using liquid handling systems to conduct affinity-based purification either in batch or tip column mode. Here, we demonstrate the capability to purify >2000 antibodies per day from microscale (1 mL) cultures...
March 1, 2018: MAbs
https://www.readbyqxmd.com/read/29485921/when-monoclonal-antibodies-are-not-monospecific-hybridomas-frequently-express-additional-functional-variable-regions
#20
Andrew R M Bradbury, Nathan D Trinklein, Holger Thie, Ian C Wilkinson, Atul K Tandon, Stephen Anderson, Catherine L Bladen, Brittany Jones, Shelley Force Aldred, Marco Bestagno, Oscar Burrone, Jennifer Maynard, Fortunato Ferrara, James S Trimmer, Janina Görnemann, Jacob Glanville, Philipp Wolf, Andre Frenzel, Julin Wong, Xin Yu Koh, Hui-Yan Eng, David Lane, Marie-Paule Lefranc, Mike Clark, Stefan Dübel
Monoclonal antibodies are commonly assumed to be monospecific, but anecdotal studies have reported genetic diversity in antibody heavy chain and light chain genes found within individual hybridomas. As the prevalence of such diversity has never been explored, we analyzed 185 random hybridomas, in a large multicenter dataset. The hybridomas analyzed were not biased towards those with cloning difficulties or known to have additional chains. Of the hybridomas we evaluated, 126 (68.1%) contained no additional productive chains, while the remaining 59 (31...
February 27, 2018: MAbs
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