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Noa Eliakim-Raz, Jihad Bishara
This review summarizes the latest advances in treating and preventing Clostridium difficile infection (CDI), the most common infectious disease cause of nosocomial diarrhea in adults in developed countries. As customary antibiotic therapies against C. difficile, metronidazole and vancomycin, are broad spectrum, they affect greatly the gut microbiota, which result in very high recurrence rates. Therefore, new strategies are researched intensively. New therapies focus on limiting further destruction of the gut microbiota or restoring the microbiota to its pre-destructed state...
May 21, 2018: Human Vaccines & Immunotherapeutics
Vahid Farrokhi, Jeffrey R Chabot, Hendrik Neubert, Zhiyong Yang
Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued as potential therapeutics for various diseases by pharmaceutical companies and academic laboratories. Many studies have demonstrated the efficacy of osteopontin inhibition in a variety of preclinical models of diseases such as rheumatoid arthritis, cancer, nonalcoholic steatohepatitis, but clinical utility has not yet been demonstrated...
May 17, 2018: Scientific Reports
Sahithi Ravuluri, Rohit Bansal, Nidhi Chhabra, Anurag S Rathore
PURPOSE: To understand non-enzymatic hydrolytic fragmentation of a monoclonal antibody therapeutic under temperature stressed conditions and investigating possible mechanism for the same. METHODS: The mAb therapeutic was incubated at 50°C in phosphate buffer at pH 6.5 and fragmentation was monitored at different ionic strengths under stressed conditions. The incubated mAb was sampled at regular time intervals by analytical Size Exclusion Chromatography (SEC). RESULTS: It was observed that 57% of the mAb product fragmented over 4 days into two fragment species - Fc-Fab and Fab with molecular weights of 97 KDa and 47 KDa, respectively, as measured by mass spectrometry (MS) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE)...
May 14, 2018: Pharmaceutical Research
Arseniy Mikhail Belov, Li Zang, Roberto Sebastiano, Marcia R Santos, David R Bush, Barry L Karger, Alexander R Ivanov
High resolution capillary zone electrophoresis - mass spectrometry (CZE-MS) has been of increasing interest for the analysis of biopharmaceuticals. In this work, a combination of middle-down and intact CZE-MS analyses has been implemented for the characterization of a biotherapeutic monoclonal antibody (mAb) with a variety of post-translational modifications (PTMs) and glycosylation structures. Middle-down and intact CZE separations were performed in an acidified methanol-water background electrolyte on a capillary with a positively-charged coating (M7C4I) coupled to an Orbitrap mass spectrometer using a commercial sheathless interface (CESI)...
May 11, 2018: Electrophoresis
Nicholas DiStasio, Stephanie Lehoux, Ali Khademhosseini, Maryam Tabrizian
Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents...
May 8, 2018: Materials
Robert Karlsson, Veronica Fridh, Åsa Frostell
Surface plasmon resonance (SPR) systems are widely used for detailed characterization of antibody activities including antigen and Fc-receptor binding. During the later stages of development, where the focus is to ensure that established critical quality attributes (CQAs) are maintained during cell culture, purification and formulation processes, analysis is simplified, and relative potencies are often determined. Here, simulation of binding data revealed that relative potency values, determined via parallel line analysis (PLA) and half maximal effective concentration (EC50) analysis accurately reflect changes in active concentration only if binding kinetics remain unchanged...
April 2018: Journal of Pharmaceutical Analysis
Catalin Doneanu, Jing Fang, Yun Alelyunas, Ying Qing Yu, Mark Wrona, Weibin Chen
The analysis of low-level (1-100 ppm) protein impurities (e.g., host-cell proteins (HCPs)) in protein biotherapeutics is a challenging assay requiring high sensitivity and a wide dynamic range. Mass spectrometry-based quantification assays for proteins typically involve protein digestion followed by the selective reaction monitoring/multiple reaction monitoring (SRM/MRM) quantification of peptides using a low-resolution (Rs ~1,000) tandem quadrupole mass spectrometer. One of the limitations of this approach is the interference phenomenon observed when the peptide of interest has the "same" precursor and fragment mass (in terms of m/z values) as other co-eluting peptides present in the sample (within a 1-Da window)...
April 17, 2018: Journal of Visualized Experiments: JoVE
Alvin J Mukalel, Brian C Evans, Kameron V Kilchrist, Eric A Dailing, Benjamin Burdette, Joyce Cheung-Flynn, Colleen M Brophy, Craig L Duvall
Herein, excipients are investigated to ameliorate the deleterious effects of lyophilization on peptide-polymer nano-polyplex (NP) morphology, cellular uptake, and bioactivity. The NPs are a previously-described platform technology for intracellular peptide delivery and are formulated from a cationic therapeutic peptide and the anionic, pH-responsive, endosomolytic polymer poly(propylacrylic acid) (PPAA). These NPs are effective when formulated and immediately used for delivery into cells and tissue, but they are not amenable to reconstitution following storage as a lyophilized powder due to aggregation...
April 27, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Hoa Le Mai, Michèle Treilhaud, Shani Leviatan Ben-Arye, Hai Yu, Hélène Perreault, Evelyn Ang, Katy Trébern-Launay, Julie Laurent, Stéphanie Malard-Castagnet, Anne Cesbron, Thi Van Ha Nguyen, Sophie Brouard, Lionel Rostaing, Pauline Houssel-Debry, Christophe Legendre, Sophie Girerd, Michèle Kessler, Emmanuel Morelon, Antoine Sicard, Valérie Garrigue, Georges Karam, Xi Chen, Magali Giral, Vered Padler-Karavani, Jean Paul Soulillou
Background: End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG)...
April 2018: Transplantation Direct
Jia Duo, JoAnne Bruno, Alexander Kozhich, Donata David-Brown, Linlin Luo, Suk Kwok, Rasa Santockyte, Jonathan Haulenbeek, Rong Liu, Lora Hamuro, Jon E Peterson, Steven Piccoli, Binodh DeSilva, Renuka Pillutla, Yan J Zhang
Ligand-binding assay (LBA) performance depends on quality reagents. Strategic reagent screening and characterization is critical to LBA development, optimization and validation. Application of advanced technologies expedites the reagent screening and assay development process. By evaluating surface plasmon resonance technology that offers high-throughput kinetic information, this article aims to provide perspectives on applying the surface plasmon resonance technology to strategic LBA critical reagent screening and characterization supported by a number of case studies from multiple biotherapeutic programs...
April 27, 2018: Bioanalysis
Anurag S Rathore, Devashish Kumar, Nikhil Kateja
Over the last several decades, researchers have time and again proposed use of non-chromatographic methods for processing of biotherapeutic products. However, chromatography continues to be the backbone of downstream processing, particularly at process scale. There are many reasons for this, critical ones being the unparalleled scalability, robustness, and selectivity that process chromatography offers over its peers. It is no surprise then that process chromatography has been a topic of major developments in resin matrix, ligand chemistry, modalities, high throughput process development, process modelling, and approaches for control...
April 27, 2018: Biotechnology Letters
Maike Schmidt, Jennie R Lill
The field of cancer immunotherapy has expanded rapidly in the past few years, with many new approaches entering the clinic for T cell mediated killing of tumors. Several of these clinical approaches involve the exploitation of a CD8 + T cell response against MHC I presented tumor antigens. Here, we describe the types of tumor antigens which are considered as targets in the design of T cell based therapeutic approaches, the rationale for targeting MHC I antigens and the analytical tools commonly employed for the discovery of MHC I presented peptides...
April 23, 2018: Journal of Proteomics
Hye-Na Kang, Ivana Knezevic
The World Health Assembly in 2014 adopted a resolution that recognized the importance of increasing access to biotherapeutic products, of improving their affordability and of ensuring their quality, safety and efficacy. Biosimilars are biotherapeutic products similar to already licensed reference products and are usually developed after patents on the original products have expired. Their introduction into the market is likely to reduce the costs of medicines substantially, thereby improving the availability of treatment for patients...
April 1, 2018: Bulletin of the World Health Organization
Deepali Rathore, Anneliese Faustino, John Schiel, Eric Pang, Michael Boyne, Sarah Rogstad
Mass spectrometry (MS) is widely used in the characterization of biomolecules including peptide and protein therapeutics. These biotechnology products have seen rapid growth over the past few decades and continue to dominate the global pharmaceutical market. Advances in MS instrumentation and techniques have enhanced protein characterization capabilities and supported an increased development of biopharmaceutical products. Areas covered: This review describes recent developments in MS-based biotherapeutic analysis including sequence determination, post-translational modifications (PTMs) and higher order structure (HOS) analysis along with improvements in ionization and dissociation methods...
April 25, 2018: Expert Review of Proteomics
Kristin Hirschberger, Anita Jarzebinska, Eva Kessel, Verena Kretzschmann, Manish K Aneja, Christian Dohmen, Annika Herrmann-Janson, Ernst Wagner, Christian Plank, Carsten Rudolph
New treatments to overcome the obstacles of conventional anti-cancer therapy are a permanent subject of investigation. One promising approach is the application of toxins linked to cell-specific ligands, so-called immunotoxins. Another attractive option is the employment of toxin-encoding plasmids. However, immunotoxins cause hepatoxicity, and DNA therapeutics, among other disadvantages, bear the risk of insertional mutagenesis. As an alternative, this study examined chemically modified mRNAs coding for diphtheria toxin, subtilase cytotoxin, and abrin-a for their ability to reduce cancer cell growth both in vitro and in vivo ...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Timothy M Pabst, Johnny Thai, Alan K Hunter
We describe a comprehensive evaluation of 12 Protein A stationary phases for capture of biotherapeutics. We first examine the morphological properties of the stationary phases using a variety of orthogonal techniques including electron microscopy, particle sizing, pressure-flow behavior, and isocratic pulse response. A panel of nine proteins spanning a wide range of structures and biochemical properties was then used to assess equilibrium uptake, mass transport, dynamic binding capacity, and elution pH. Process performance and product quality were also examined under realistic bioprocess conditions using clarified mammalian cell culture broth...
April 7, 2018: Journal of Chromatography. A
Kristina J Allan, Douglas J Mahoney, Stephen D Baird, Charles A Lefebvre, David F Stojdl
High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact virus replication. Here we present the application of this technology to uncovering host targets that specifically modulate the replication of Maraba virus, an oncolytic rhabdovirus, and vaccinia virus with the goal of enhancing therapy. While the protocol has been tested for use with oncolytic Maraba virus and oncolytic vaccinia virus, this approach is applicable to other oncolytic viruses and can also be utilized for identifying host targets that modulate virus replication in mammalian cells in general...
April 3, 2018: Journal of Visualized Experiments: JoVE
Lijuan Jiang, Xin Liang, Gan Liu, Yun Zhou, Xinyu Ye, Xiuli Chen, Qianwei Miao, Li Gao, Xudong Zhang, Lin Mei
Protein nanocapsules have exhibited promising potential applications in the field of protein drug delivery. A major issue with various promising nano-sized biotherapeutics including protein nanocapsules is that owing to their particle size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. In addition, many nano-sized biotherapeutics could be also sequestered by autophagosomes and degraded through the autolysosomal pathway...
November 2018: Drug Delivery
Kirsten M Mease, Amy L Kimzey, Janice A Lansita
The observation of an infusion reaction (IR) in a nonclinical study can cause concern among investigators and regulators in the development of biotherapeutics. Biomarkers can be informative to determine whether the reactions are immune-mediated or test-article related and if there is a potential risk to human subjects. IRs encompass a broad range of adverse events with a variety of triggers; the focus of this paper is IRs due to cytokine release syndrome or immune complex formation and the associated biomarkers...
June 2017: Current Opinion in Toxicology
Corey E Reed, Jennifer Fournier, Nikolaos Vamvoukas, Stephan M Koza
N-Glycan analysis is routinely performed for biotherapeutic protein characterization. A recently introduced N-glycan analysis kit using RapiFluor-MS (RFMS) labeling provides time savings over reductive amination labeling methods while also providing enhanced fluorescence (FLR) and mass spectrometry (MS) responses. This article demonstrates the semiautomation of this kit using an Andrew Alliance pipetting robot that promises further gains in productivity. This robotic platform uses standard manual pipettors and an optically guided arm to facilitate the automation of manual procedures...
March 1, 2018: SLAS Technology
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