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https://www.readbyqxmd.com/read/29341500/investigation-of-the-free-heavy-chain-homodimers-of-a-monoclonal-antibody
#1
Hyo Helen Chung, Lynette Buck, Kristi Daris, Brent Welborn, Quanzhou Luo, Jette Wypych
Monoclonal antibodies (mAbs) are composed of two heavy chain (HC) and two light chain (LC) polypeptides. The proper folding and assembly of HC and LC is critical for antibody production. Current dogma indicates that the free HCs are retained in the endoplasmic reticulum (ER) unless assembled with LCs into antibodies, while the LCs on the other hand can be secreted as free monomer or dimer molecules. In this study, high levels of extracellular HC homodimers (7-45%) were observed in the cell culture media during cell line development for mAb1...
January 17, 2018: Biotechnology Progress
https://www.readbyqxmd.com/read/29324282/influence-of-glycan-modification-on-igg1-biochemical-and-biophysical-properties
#2
Jake W Pawlowski, Adriana Bajardi-Taccioli, Damian Houde, Marina Feschenko, Tyler Carlage, Igor A Kaltashov
Monoclonal antibodies (mAbs) are the fastest growing class of biopharmaceuticals. The specific therapeutic tasks vary among different mAbs, which may include neutralization of soluble targets, activation of cytotoxic pathways, targeted drug delivery, and diagnostic imaging. The specific therapeutic goal defines which interactions of the antibody with its multiple physiological partners are most critical for function, and which ones are irrelevant or indeed detrimental. In this work, we explored the ability of the glycan chains to affect IgG1 interaction with two key receptor families, FcRn and γ-type Fc receptors, as well as the influence of glycan composition on the conformation and stability of the antibody molecule...
January 3, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29322349/development-of-a-chemically-defined-platform-fed-batch-culture-media-for-monoclonal-antibody-producing-cho-cell-lines-with-optimized-choline-content
#3
Shinobu Kuwae, Ichiko Miyakawa, Tomohiro Doi
A chemically defined platform basal medium and feed media were developed using a single Chinese hamster ovary (CHO) cell line that produces a monoclonal antibody (mAb). Cell line A, which showed a peak viable cell density of 5.9 × 106 cells/mL and a final mAb titer of 0.5 g/L in batch culture, was selected for the platform media development. Stoichiometrically balanced feed media were developed using glucose as an indicator of cell metabolism to determine the feed rates of all other nutrients. A fed-batch culture of cell line A using the platform fed-batch medium yielded a 6...
January 11, 2018: Cytotechnology
https://www.readbyqxmd.com/read/29315494/isotype-dependent-on-column-non-reversible-aggregation-of-monoclonal-antibodies
#4
Monika Farys, Daniel Gibson, Alan Lewis, Will Lewis, Richard Kucia-Tran
Monoclonal antibodies of the IgG2 and IgG4 isotype were found to exhibit an increased propensity for displaying two-peak elution profiles during cation exchange chromatography. In some cases, this two-peak elution profile also resulted in the formation of non-reversible mAb aggregates. Comparison of IgG1, IgG2 and IgG4 molecules with the same variable region reveals that the two-peak behaviour is predominantly mediated by the constant region and most likely the lower CH1, hinge and upper CH2 regions of the mAb...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29315487/using-extensional-flow-to-reveal-diverse-aggregation-landscapes-for-three-igg1-molecules
#5
Leon F Willis, Amit Kumar, John Dobson, Nick Bond, David Lowe, Richard Turner, Sheena E Radford, Nikil Kapur, David J Brockwell
Monoclonal antibodies (mAbs) currently dominate the biopharmaceutical sector due to their potency and efficacy against a range of disease targets. These proteinaceous therapeutics are, however, susceptible to unfolding, mis-folding and aggregation by environmental perturbations. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation and storage. Hydrodynamic forces have also been linked to aggregation, but the ability of different flow fields (e.g. shear and extensional flow) to trigger aggregation has remained unclear...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29313446/monoclonal-antibody-higher-order-structure-analysis-by-high-throughput-protein-conformational-array
#6
Yuanli Song, Deqiang Yu, Mukesh Mayani, Nesredin Mussa, Zheng Jian Li
The elucidation of antibody higher order structure (HOS) is critical in therapeutic antibody development. Since HOS determines the protein bioactivity and chemo-physical properties, this knowledge can help to ensure that the safety and efficacy attributes are not compromised. Protein conformational array (PCA) is a novel method for determining the HOS of monoclonal antibodies. Previously, we successfully utilized an enzyme-linked immunosorbent assay (ELISA)-based PCA along with other bioanalytical tools to elucidate the structures of antibody aggregates...
January 9, 2018: MAbs
https://www.readbyqxmd.com/read/29281723/human-immunodeficiency-virus-type-1-hiv-1-evades-antibody-dependent-phagocytosis
#7
Johannes S Gach, Margaux Bouzin, Marcus P Wong, Veronika Chromikova, Andrea Gorlani, Kuan-Ting Yu, Brijesh Sharma, Enrico Gratton, Donald N Forthal
Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV-1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV-1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1...
December 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29280480/identification-of-process-conditions-influencing-protein-aggregation-in-chinese-hamster-ovary-cell-culture
#8
Albert Jesuran Paul, René Handrick, Sybille Ebert, Friedemann Hesse
Protein aggregation of monoclonal antibodies (mAbs) is a common phenomenon associated with the production of these biopharmaceuticals. These aggregates can lead to adverse side effects in patients upon administration, thus expensive downstream processing steps to remove the higher molecular weight species are inevitable. A preferable approach is to reduce the level of aggregation during bioprocessing by a careful adjustment of critical process parameters. Recently, new analytical methods enabled characterization of mAb aggregation during bioprocessing of mammalian cells...
December 27, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29277294/structural-basis-of-enhanced-crystallizability-induced-by-a-molecular-chaperone-for-antibody-antigen-binding-fragments
#9
June Ereño-Orbea, Taylor Sicard, Hong Cui, Jacob Carson, Pim Hermans, Jean-Philippe Julien
Monoclonal antibodies (mAbs) constitute one of the largest groups of drugs to treat cancers and immune disorders, and are guiding the design of vaccines against infectious diseases. Fragments antigen-binding (Fabs) have been preferred over mAbs for the structural characterization of antibody-antigen complexes due to their relatively low flexibility. Nonetheless, Fabs often remain challenging to crystallize because of the surface characteristics of complementary determining regions and the residual flexibility in the hinge region between the variable and constant domains...
December 22, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29240412/integration-of-on-column-chemical-reactions-in-protein-characterization-by-lc-ms-cross-path-reactive-chromatography
#10
Jake Pawlowski, Ian Carrick, Igor A Kaltashov
Profiling of complex proteins by means of mass spectrometry (MS) frequently requires that certain chemical modifications of their covalent structure (e.g., reduction of disulfide bonds) be carried out prior to the MS or MS/MS analysis. Traditionally, these chemical reactions take place in the off-line mode to allow the excess reagents (the majority of which interfere with the MS measurements and degrade the analytical signal) to be removed from the protein solution prior to MS measurements. In addition to a significant increase in the analysis time, chemical reactions may result in a partial or full loss of the protein if the modifications adversely affect its stability, e...
December 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29229331/an-integrated-precipitation-and-ion-exchange-chromatography-process-for-antibody-manufacturing-process-development-strategy-and-continuous-chromatography-exploration
#11
Steffen Großhans, Gang Wang, Christian Fischer, Jürgen Hubbuch
In the past decades, research was carried out to find cost-efficient alternatives to Protein A chromatography as a capture step in monoclonal antibody (mAb) purification processes. In this work, polyethylene glycol (PEG) precipitation has shown promising results in the case of mAb yield and purity. Especially with respect to continuous processing, PEG precipitation has many advantages, like low cost of goods, simple setup, easy scalability, and the option to handle perfusion reactors. Nevertheless, replacing Protein A has the disadvantage of renouncing a platform unit operation as well...
December 6, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/29220376/c5a-and-c5ar-are-elevated-in-joints-of-rheumatoid-and-psoriatic-arthritis-patients-and-c5ar-blockade-attenuates-leukocyte-migration-to-synovial-fluid
#12
Lars Hornum, Anker Jon Hansen, Ditte Tornehave, Marianne Scheel Fjording, Paula Colmenero, Inger Falbe Wätjen, Niels Henrik Søe Nielsen, Henning Bliddal, Else Marie Bartels
Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects...
2017: PloS One
https://www.readbyqxmd.com/read/29182876/solid-state-hydrogen-deuterium-exchange-mass-spectrometry-correlation-of-deuterium-uptake-and-long-term-stability-of-lyophilized-monoclonal-antibody-formulations
#13
Balakrishnan S Moorthy, Isidro E Zarraga, Lokesh Kumar, Benjamin T Walters, Pierre Goldbach, Elizabeth M Topp, Andrea Allmendinger
Solid state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) has been used to assess protein conformation and matrix interactions in lyophilized solids. ssHDX-MS metrics have been previously correlated to the formation of aggregates of lyophilized myoglobin on storage. Here, ssHDX-MS was applied to lyophilized monoclonal antibody (mAb) formulations and correlated to their long-term stability. After exposing lyophilized samples to D2O(g), the amount of deuterium incorporated at various time points was determined by mass spectrometry for four different lyophilized mAb formulations...
November 28, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29181010/crystallizable-fragment-glycoengineering-for-therapeutic-antibodies-development
#14
REVIEW
Wei Li, Zhongyu Zhu, Weizao Chen, Yang Feng, Dimiter S Dimitrov
Monoclonal antibody (mAb)-based therapeutics are the fastest growing class of human pharmaceuticals. They are typically IgG1 molecules with N-glycans attached to the N297 residue on crystallizable fragment (Fc). Different Fc glycoforms impact their effector function, pharmacokinetics, stability, aggregation, safety, and immunogenicity. Fc glycoforms affect mAbs effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) by modulating the Fc-FcγRs and Fc-C1q interactions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29168704/extracellular-polymeric-substance-production-in-high-rate-algal-oxidation-ponds
#15
Taobat A Jimoh, A Keith Cowan
Integrated algal pond systems (IAPSs) combine anaerobic and aerobic bioprocesses to affect sewage treatment. The present work describes the isolation and partial characterisation of soluble extracellular polymeric substances (EPSs) associated with microalgal bacterial flocs (MaB-flocs) generated in high rate algal oxidation ponds (HRAOPs) of an IAPS treating domestic sewage. Productivity and change in MaB-flocs concentration, measured as mixed liquor suspended solids (MLSS) between morning (MLSSAM) and evening (MLSSPM) were monitored and the substructure of the MaB-flocs matrix examined by biochemical analysis and Fourier transform infrared spectroscopy (FT-IR)...
November 2017: Water Science and Technology: a Journal of the International Association on Water Pollution Research
https://www.readbyqxmd.com/read/29110285/chemical-and-biophysical-characteristics-of-monoclonal-antibody-solutions-containing-aggregates-formed-during-metal-catalyzed-oxidation
#16
Linda O Narhi, Quanzhou Luo, Jette Wypych, Riccardo Torosantucci, Andrea Hawe, Kiyoshi Fujimori, Yasser Nashed-Samuel, Vibha Jawa, Marisa K Joubert, Wim Jiskoot
PURPOSE: To physicochemically characterize and compare monoclonal antibody (mAb) solutions containing aggregates generated via metal catalyzed oxidation (MCO). METHODS: Two monoclonal IgG2s (mAb1 and mAb2) and one monoclonal IgG1 (rituximab) were exposed to MCO with the copper/ascorbic acid oxidative system, by using several different methods. The products obtained were characterized by complementary techniques for aggregate and particle analysis (from oligomers to micron sized species), and mass spectrometry methods to determine the residual copper content and chemical modifications of the proteins...
November 6, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/29090969/expression-of-cat-podoplanin-in-feline-squamous-cell-carcinomas
#17
Shunsuke Itai, Shinji Yamada, Mika K Kaneko, Hiroyuki Harada, Yumiko Kagawa, Satoru Konnai, Yukinari Kato
Oral squamous cell carcinoma is an aggressive tumor in cats; however, molecular-targeted therapies against this tumor, including antibody therapy, have not been developed. Sensitive and specific monoclonal antibodies (mAbs) against highly expressed membrane proteins are needed to develop antibody therapies. Podoplanin, a type I transmembrane glycoprotein, is expressed in many human malignant tumors, including brain tumor, esophageal cancer, lung cancer, mesothelioma, and oral cancer. Podoplanin binds to C-type lectin-like receptor-2 (CLEC-2) and activates platelet aggregation, which is involved in cancer metastasis...
November 1, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/29055527/multi-state-steric-mass-action-model-and-case-study-on-complex-high-loading-behavior-of-mab-on-ion-exchange-tentacle-resin
#18
Juliane Diedrich, William Heymann, Samuel Leweke, Stephen Hunt, Robert Todd, Christian Kunert, Will Johnson, Eric von Lieres
Tentacle resins for IEX are increasingly applied in preparative chromatography for their higher selectivity and higher capacities in comparison to IEX resins without tentacles. However, tentacle resins are often observed to cause unusual elution behavior of monoclonal antibodies under high loading conditions. Understanding this elution behavior is important for a quality by design approach, as it is now mandated by regulatory agencies. A model-based analysis of load, wash and gradient elution is performed for a monoclonal antibody (mAb) on Fractogel SO3(-)...
September 20, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/29054386/interlaced-size-exclusion-chromatography-for-faster-protein-analysis
#19
Julia Kahle, Hermann Wätzig
In this research note, interlaced Size Exclusion Chromatography (SEC) is used to shorten the duration of protein analysis. The applied method has a threefold higher sample throughput than comparable ones using conventional SEC. Further important advantages are the identical area's precision and the preservation of protein stability. Two different applications are presented where a short time interval of analysis is very important. One application is the determination of aggregates of monoclonal antibodies (mAbs)...
October 17, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29037466/the-use-of-a-groel-bli-biosensor-to-rapidly-assess-pre-aggregate-populations-for-antibody-solutions-exhibiting-different-stability-profiles
#20
Samantha E Pace, Sangeeta B Joshi, Reza Esfandiary, Robert Stadelman, Steven M Bishop, C R Middaugh, Mark Fisher, David B Volkin
An automated method using biotinylated GroEL-streptavidin biosensors with Bio-Layer Interferometry (GroEL-BLI) was evaluated to detect the formation of transiently formed, pre-aggregate species in various pharmaceutically relevant monoclonal antibody (mAb) samples. The relative aggregation propensity of various IgG1 and IgG4 mAbs was rank-ordered using the GroEL-BLI biosensor method, and the least stable IgG4 mAb was subjected to different stresses including elevated temperatures, acidic pH, and addition of guanidine-HCl...
October 13, 2017: Journal of Pharmaceutical Sciences
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