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https://www.readbyqxmd.com/read/28212986/correlating-the-effects-of-antimicrobial-preservatives-on-conformational-stability-aggregation-propensity-and-backbone-flexibility-of-an-igg1-monoclonal-antibody
#1
Jayant Arora, Sangeeta B Joshi, C Russell Middaugh, David D Weis, David B Volkin
Multi-dose formulations of biotherapeutics, which offer better dosage management and reduced production costs, require the addition of antimicrobial preservatives (APs). APs have been shown, however, to decrease protein stability in solution and cause protein aggregation. In this report, the effect of four APs, m-cresol, phenol, phenoxyethanol and benzyl alcohol, on conformational stability, aggregation propensity and backbone flexibility of an IgG1 monoclonal antibody, mAb-4, is investigated. Compared to no preservative control, each of the APs decreased the conformational stability of mAb-4 as measured by DSC and extrinsic fluorescence spectroscopy...
February 14, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28208831/resveratrol-and-grape-extract-loaded-solid-lipid-nanoparticles-for-the-treatment-of-alzheimer-s-disease
#2
Joana A Loureiro, Stephanie Andrade, Ana Duarte, Ana Rute Neves, Joana Fontes Queiroz, Cláudia Nunes, Emmanuel Sevin, Laurence Fenart, Fabien Gosselet, Manuel A N Coelho, Maria Carmo Pereira
The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated...
February 13, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28186329/effects-of-antibody-disulfide-bond-reduction-on-purification-process-performance-and-final-drug-substance-stability
#3
Wai Keen Chung, Brian Russell, Yanhong Yang, Michael Handlogten, Suzanne Hudak, Mingyan Cao, Jihong Wang, David Robbins, Sanjeev Ahuja, Min Zhu
Antibody disulfide bond reduction during monoclonal antibody (mAb) production is a phenomenon that has been attributed to the reducing enzymes from CHO cells acting on the mAb during the harvest process. However, the impact of antibody reduction on the downstream purification process has not been studied. During the production of an IgG2 mAb, antibody reduction was observed in the harvested cell culture fluid (HCCF), resulting in high fragment levels. In addition, aggregate levels increased during the low pH treatment step in the purification process...
February 10, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28186164/a-new-approach-to-quantification-of-mab-aggregates-using-peptide-affinity-probes
#4
Crystal S F Cheung, Kyle W Anderson, Pooja M Patel, Keale L Cade, Karen W Phinney, Illarion V Turko
Using mAbs as therapeutic molecules is complicated by the propensity of mAbs to aggregate at elevated concentrations, which can lead to a variety of adverse events in treatment. Here, we describe a proof-of-concept for new methodology to detect and quantify mAb aggregation. Assay development included using an aggregated mAb as bait for screening of phage display peptide library and identifying those peptides with random sequence which can recognize mAb aggregates. Once identified, the selected peptides can be used for developing quantitative methods to assess mAb aggregation...
February 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28176518/main-quality-attributes-of-monoclonal-antibodies-and-effect-of-cell-culture-components
#5
Fatemeh Torkashvand, Behrouz Vaziri
The culture media optimization is an inevitable part of upstream process development in therapeutic monoclonal antibodies (mAbs) production. The quality by design (QbD) approach defines the assured quality of the final product through the development stage. An important step in QbD is determination of the main quality attributes. During the media optimization, some of the main quality attributes such as glycosylation pattern, charge variants, aggregates, and low-molecular-weight species, could be significantly altered...
8, 2017: Iranian Biomedical Journal
https://www.readbyqxmd.com/read/28157429/chimeric-anti-human-podoplanin-antibody-nz-12-of-lambda-light-chain-exerts-higher-antibody-dependent-cellular-cytotoxicity-and-complement-dependent-cytotoxicity-compared-with-nz-8-of-kappa-light-chain
#6
Mika K Kaneko, Shinji Abe, Satoshi Ogasawara, Yuki Fujii, Shinji Yamada, Takeshi Murata, Hiroaki Uchida, Hideaki Tahara, Yasuhiko Nishioka, Yukinari Kato
Podoplanin (PDPN), a type I transmembrane 36-kDa glycoprotein, is expressed not only in normal cells, such as renal epithelial cells (podocytes), lymphatic endothelial cells, and pulmonary type I alveolar cells, but also in cancer cells, including brain tumors and lung squamous cell carcinomas. Podoplanin activates platelet aggregation by binding to C-type lectin-like receptor-2 (CLEC-2) on platelets, and the podoplanin/CLEC-2 interaction facilitates blood/lymphatic vessel separation. We previously produced neutralizing anti-human podoplanin monoclonal antibody (mAb), clone NZ-1 (rat IgG2a, lambda), which neutralizes the podoplanin/CLEC-2 interaction and inhibits platelet aggregation and cancer metastasis...
February 3, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28137697/bulky-polar-additives-that-greatly-reduce-the-viscosity-of-concentrated-solutions-of-therapeutic-monoclonal-antibodies
#7
Alyssa M Larson, Alisha K Weight, Kevin Love, Amanda Bonificio, Charles R Wescott, Alexander M Klibanov
The viscosity of concentrated aqueous solutions of three clinical monoclonal antibodies (mAbs), Erbitux(®), Herceptin(®), and Rituxan(®) has been reduced up to over 10 fold by adding certain bulky polar additives instead of saline at isotonic levels. Since these additives are also found not to compromise mAbs' stability against aggregation induced by stresses, a drug-delivery modality switch from intravenous infusions to more convenient and inexpensive parenteral options like subcutaneous injections may become possible...
January 27, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28122739/integrin-psi-domain-has-endogenous-thiol-isomerase-function-and-is-a-novel-target-for-anti-platelet-therapy
#8
Guangheng Zhu, Qing Zhang, Emily C Reddy, Naadiya Carrim, Yunfeng Chen, Xiaohong Ruby Xu, Miao Xu, Yiming Wang, Yan Hou, Li Ma, Yan Li, Min Rui, Tania Petruzziello, Christopher Lavalle, Tyler W Stratton, Xi Lei, Adili Reheman, Pingguo Chen, Cheng Zhu, John A Wilkins, Richard O Hynes, John Freedman, Heyu Ni
Integrins are a large family of heterodimeric transmembrane receptors differentially expressed on almost all metazoan cells. Integrin β subunits contain a highly conserved plexin-semaphorin-integrin (PSI) domain. The CXXC motif, the active site of protein-disulfide-isomerase (PDI) family, is expressed twice in this domain of all integrins across species. However, the role of PSI domain in integrins and whether it contains thiol-isomerase activity have not been explored. Here, recombinant PSI domains of murine β3, human β1 and β2 integrins were generated and their PDI-like activity was demonstrated by refolding of reduced/denatured RNase...
January 25, 2017: Blood
https://www.readbyqxmd.com/read/28114383/immunogenicity-of-isogenic-igg-in-aggregates-and-immune-complexes
#9
J Benjamin St Clair, Thiago Detanico, Katja Aviszus, Greg A Kirchenbaum, Merry Christie, John F Carpenter, Lawrence J Wysocki
A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against IgG in various physical states, we developed an adoptive transfer model using CD4+ T cells specific for a Vκ region-derived peptide in the hapten-specific IgG mAb 36-71. We found that heat-aggregated or immune complexes (IC) of mAb 36-71 elicited anti-idiotypic (anti-Id) antibodies, while the deaggregated form was tolerogenic...
2017: PloS One
https://www.readbyqxmd.com/read/28101903/development-and-characterization-of-anti-glycopeptide-monoclonal-antibodies-against-human-podoplanin-using-glycan-deficient-cell-lines-generated-by-crispr-cas9-and-talen
#10
Mika K Kaneko, Takuro Nakamura, Ryusuke Honma, Satoshi Ogasawara, Yuki Fujii, Shinji Abe, Michiaki Takagi, Hiroyuki Harada, Hiroyoshi Suzuki, Yasuhiko Nishioka, Yukinari Kato
Human podoplanin (hPDPN), which binds to C-type lectin-like receptor-2 (CLEC-2), is involved in platelet aggregation and cancer metastasis. The expression of hPDPN in cancer cells or cancer-associated fibroblasts indicates poor prognosis. Human lymphatic endothelial cells, lung-type I alveolar cells, and renal glomerular epithelial cells express hPDPN. Although numerous monoclonal antibodies (mAbs) against hPDPN are available, they recognize peptide epitopes of hPDPN. Here, we generated a novel anti-hPDPN mAb, LpMab-21...
January 19, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28089934/evaluation-of-aggregate-and-silicone-oil-counts-in-pre-filled-siliconized-syringes-an-orthogonal-study-characterising-the-entire-subvisible-size-range
#11
Maryam Shah, Zahra Rattray, Katie Day, Shahid Uddin, Robin Curtis, Christopher F van der Walle, Alain Pluen
Characterisation of particulates in therapeutic monoclonal antibody (mAb) formulations is routinely extended to the sub-visible size-range (0.1-10μm). Additionally, with the increased use of pre-filled syringes (PFS), particle differentiation is required between proteinaceous and non-proteinaceous particles such as silicone-oil droplets. Here, three orthogonal techniques: Raster Image Correlation Spectroscopy (RICS), Resonance Mass Measurements (RMM) and Micro-Flow Imaging (MFI), were evaluated with respect to their sub-visible particle measurement and characterisation capabilities...
January 9, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28054640/honokiol-as-a-specific-collagen-receptor-glycoprotein-vi-antagonist-on-human-platelets-functional-ex-vivo-and-in-vivo-studies
#12
Tzu-Yin Lee, Chao-Chien Chang, Wan-Jung Lu, Ting-Lin Yen, Kuan-Hung Lin, Pitchairaj Geraldine, Jiun-Yi Li, Joen-Rong Sheu
Honokiol, derived from Magnolia officinalis, has various pharmacological properties. Platelet activation plays a critical role in cardiovascular diseases. Honokiol has been reported to inhibit collagen-stimulated rabbit platelet aggregation. However, detailed further studies on the characteristics and functional activity of honokiol in platelet activation are relatively lacking. In the present study, honokiol specifically inhibited platelet aggregation and Ca(+2) ion mobilization stimulated with collagen or convulxin, an agonist of glycoprotein (GP) VI, but not with aggretin, an agonist of integrin α2β1...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27982442/assessment-of-disulfide-and-hinge-modifications-of-monoclonal-antibodies
#13
REVIEW
Bernd Moritz, Jan Olaf Stracke
During the last years there was a substantial increase in the use of antibodies and related proteins as therapeutics. The emphasis of the pharmaceutical industry is on IgG1, IgG2 and IgG4 antibodies which are therefore in the focus of this article. In order to ensure appropriate quality control of such biopharmaceuticals, deep understanding of their chemical degradation pathways and the resulting impact on potency, pharmacokinetics and safety is required. Criticality of modifications may be specific for individual antibodies and has to be assessed for each molecule...
December 16, 2016: Electrophoresis
https://www.readbyqxmd.com/read/27964939/shipping-induced-aggregation-in-therapeutic-antibodies-utilization-of-a-scale-down-model-to-assess-degradation-in-mabs
#14
Marianna L Fleischman, Jonathan Chung, Eden P Paul, Rachael A Lewus
It is vital to understand the impact of transportation on monoclonal antibody (mAb) product quality during drug product development. Fully representative real-time shipment studies are resource intensive, so in this work we studied laboratory agitation methods to mimic the effect of real-time shipment on aggregation, specifically sub-visible particle formation. The agitation methods studied include a rotator, orbital shaker, vortexer, and shipping simulator vibration table. The simulator is able to predict the particle formation behavior during real-time shipment for a number of mAbs in vial and pre-filled syringe (PFS) configurations, with a correlation of about 90%, while the other methods of agitation were inconsistent...
December 10, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27943050/in-vitro-evaluation-of-beneficial-properties-of-bacteriocinogenic-lactobacillus-plantarum-st8sh
#15
Svetoslav Dimitrov Todorov, Wilhelm Holzapfel, Luis Augusto Nero
Lactobacillus plantarum ST8Sh, isolated from Bulgarian salami "shpek" and previously characterized as bacteriocin producer, was evaluated for its beneficial properties. Based on the PCR analysis, Lb. plantarum ST8Sh was shown to host a gene related to the production of adhesion proteins such as Mab, Mub, EF, and PrgB. Genetic and physiological tests suggest Lb. plantarum ST8Sh to represent a potential probiotic candidate, including survival in the presence of low levels of pH and high levels of ox bile, production of β-galactosidase, bile salt deconjugation, high level of hydrophobicity, functional auto- and co-aggregation properties, and adhesion to cell lines...
December 10, 2016: Probiotics and Antimicrobial Proteins
https://www.readbyqxmd.com/read/27939321/transfer-of-a-three-step-mab-chromatography-process-from-batch-to-continuous-optimizing-productivity-to-minimize-consumable-requirements
#16
Xhorxhi Gjoka, Rene Gantier, Mark Schofield
The goal of this study was to adapt a batch mAb purification chromatography platform for continuous operation. The experiments and rationale used to convert from batch to continuous operation are described. Experimental data was used to design chromatography methods for continuous operation that would exceed the threshold for critical quality attributes and minimize the consumables required as compared to batch mode of operation. Four unit operations comprising of Protein A capture, viral inactivation, flow-through anion exchange (AEX), and mixed-mode cation exchange chromatography (MMCEX) were integrated across two Cadence BioSMB PD multi-column chromatography systems in order to process a 25L volume of harvested cell culture fluid (HCCF) in less than 12h...
January 20, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/27914608/evaluation-of-size-exclusion-chromatography-columns-packed-with-sub-3%C3%AE-m-particles-for-the-analysis-of-biopharmaceutical-proteins
#17
Alexandre Goyon, Alain Beck, Olivier Colas, Koen Sandra, Davy Guillarme, Szabolcs Fekete
The aim of this study was to evaluate the practical possibilities and limitations of several recently introduced size exclusion chromatographic (SEC) columns of 150×4.6mm, sub-3μm (Agilent AdvanceBioSEC 2.7μm, Tosoh TSKgel UP-SW3000 2.0μm, Phenomenex Yarra SEC X-150 1.8μm and Waters Acquity BEH200 1.7μm) for the separation of biopharmaceutical proteins. For this purpose, some model proteins were tested, as well as several commercial therapeutic monoclonal antibodies (mAbs) and antibody-drug-conjugates (ADCs)...
November 27, 2016: Journal of Chromatography. A
https://www.readbyqxmd.com/read/27855600/optimization-on-fc-for-improvement-of-stability-and-aggregation-resistance
#18
Xiaobo Chen, Fang Zeng, Tao Huang, Liang Cheng, Huan Liu, Rui Gong
Fc-based therapeutics including therapeutic full-size monoclonal antibodies (mAbs) and Fc-fusion proteins represent fastest-growing market in biopharmaceutical industrial. However, one major challenge during development of Fc-based therapeutics is how to maintain their efficacy in clinic use. Many factors may lead to failure in final marketing. For example, the stability and aggregation resistance might not be high enough for bearing the disadvantages during fermentation, purification, formulation, storage, shipment and other steps in manufacture and sale...
November 17, 2016: Current Pharmaceutical Biotechnology
https://www.readbyqxmd.com/read/27789805/processing-impact-on-monoclonal-antibody-drug-products-protein-subvisible-particulate-formation-induced-by-grinding-stress
#19
Benson Gikanga, Devon Roshan-Eisner, Robert Ovadia, Eric S Day, Oliver Boris Stauch, Yuh-Fun Maa
Subvisible particle formation in monoclonal antibody (mAb) drug product resulting from mixing and filling operations represents a significant processing risk that can lead to filter fouling and thereby lead to process delays or failures. Several previous studies from our lab and others demonstrated the formation of subvisible particulates in mAb formulations resulting from mixing operations using some bottom-mounted mixers or stirrer bars. It was hypothesized that the stress (e.g. shear/cavitation) derived from tight clearance and/or close contact between the impeller and shaft was responsible for SvP generation...
October 27, 2016: PDA Journal of Pharmaceutical Science and Technology
https://www.readbyqxmd.com/read/27788030/pmab-38-recognizes-canine-podoplanin-of-squamous-cell-carcinomas
#20
Mika K Kaneko, Ryusuke Honma, Satoshi Ogasawara, Yuki Fujii, Takuro Nakamura, Noriko Saidoh, Michiaki Takagi, Yumiko Kagawa, Satoru Konnai, Yukinari Kato
Podoplanin, a type I transmembrane protein, is expressed in lymphatic endothelial cells. Although we previously developed an anticanine podoplanin monoclonal antibody (mAb), PMab-38, immunohistochemistry (IHC) showed that it did not react with canine lymphatic endothelial cells. Here, we determined whether PMab-38 recognizes canine podoplanin of squamous cell carcinomas (SCCs) and clarified its epitope. In IHC, PMab-38 reacted with 83% of SCCs (15/18 cases). Flow cytometry showed that the epitope of PMab-38 was different from that of the platelet aggregation-stimulating domain of the N-terminus, which was detected by almost all antipodoplanin mAbs such as D2-40 or NZ-1...
October 2016: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
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