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Kelley M Heffner, Qiong Wang, Deniz Baycin Hizal, Özge Can, Michael J Betenbaugh
Mammalian expression systems such as Chinese hamster ovary (CHO), mouse myeloma (NS0), and human embryonic kidney (HEK) cells serve a critical role in the biotechnology industry as the production host of choice for recombinant protein therapeutics. Most of the recombinant biologics are glycoproteins that contain complex oligosaccharide or glycan attachments representing a principal component of product quality. Both N-glycans and O-glycans are present in these mammalian cells, but the engineering of N-linked glycosylation is of critical interest in industry and many efforts have been directed to improve this pathway...
March 13, 2018: Advances in Biochemical Engineering/biotechnology
Chirom Aarti, Ameer Khusro, Rakesh Varghese, Mariadhas Valan Arasu, Paul Agastian, Naïf Abdullah Al-Dhabi, Soundharrajan Ilavenil, Ki Choon Choi
OBJECTIVE: To investigate the probiotic characteristics, anti-Candida activity, and antibiofilm attributes of Hentak derived Lactobacillus pentosus strain LAP1. DESIGN: The probiotic properties of strain LAP1 was depicted by adapting standard protocols. The anti-Candida and antibiofilm properties of isolate were determined using agar well diffusion assay and ELISA reader test, respectively. The time-kill assay was performed using viable colony count assay. Further, the co-aggregation property of strain LAP1 was determined based on standard methodology...
February 23, 2018: Archives of Oral Biology
Beata Borza, Marton Szigeti, Akos Szekrenyes, Laszlo Hajba, Andras Guttman
The carbohydrate moieties on the polypeptide chains in most glycoprotein based biotherapeutics and their biosimilars play essential roles in such major mechanisms of actions as antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, anti-inflammatory functions and serum clearance. In addition, alteration in glycosylation may influence the safety and efficacy of the product. Glycosylation, therefore, is considered as one of the important critical quality attributes of glycoprotein biotherapeutics, and consequently for their biosimilar counterparts...
February 15, 2018: Journal of Pharmaceutical and Biomedical Analysis
Benjamin Schubert, Charlotta Schärfe, Pierre Dönnes, Thomas Hopf, Debora Marks, Oliver Kohlbacher
Immunogenicity is a major problem during the development of biotherapeutics since it can lead to rapid clearance of the drug and adverse reactions. The challenge for biotherapeutic design is therefore to identify mutants of the protein sequence that minimize immunogenicity in a target population whilst retaining pharmaceutical activity and protein function. Current approaches are moderately successful in designing sequences with reduced immunogenicity, but do not account for the varying frequencies of different human leucocyte antigen alleles in a specific population and in addition, since many designs are non-functional, require costly experimental post-screening...
March 2, 2018: PLoS Computational Biology
Yotis A Senis, Alastair J Barr
Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the "inside-out" approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Marion David, Pascaline Lécorché, Maxime Masse, Aude Faucon, Karima Abouzid, Nicolas Gaudin, Karine Varini, Fanny Gassiot, Géraldine Ferracci, Guillaume Jacquot, Patrick Vlieghe, Michel Khrestchatisky
Insufficient membrane penetration of drugs, in particular biotherapeutics and/or low target specificity remain a major drawback in their efficacy. We propose here the rational characterization and optimization of peptides to be developed as vectors that target cells expressing specific receptors involved in endocytosis or transcytosis. Among receptors involved in receptor-mediated transport is the LDL receptor. Screening complex phage-displayed peptide libraries on the human LDLR (hLDLR) stably expressed in cell lines led to the characterization of a family of cyclic and linear peptides that specifically bind the hLDLR...
2018: PloS One
Yining Xu, Yaxian Zheng, Lei Wu, Xi Zhu, Zhirong Zhang, Yuan Huang
Although nanoparticles (NPs) have been demonstrated as promising tools for improving oral absorption of biotherapeutics, most of them still have very limited oral bioavailability. Lyso-endosomal degradation in epithelial cells is one of important but often-neglected physiological barriers, limiting the transport of cargoes across the intestinal epithelium. We herein reported a solid lipid nanoparticle (SLN) platform with a unique feature of endosomal escape for oral protein drug delivery. The SLNs consisted of a solid-lipid shell, which contained an endosomal escape agent (GLFEAIEGFIENGWEGMIDGWYG, HA2), and an aqueous core that loaded with insulin (INS HA2-O-SLNs)...
February 27, 2018: ACS Applied Materials & Interfaces
Cristina Montealegre, Christian Neusüß
Imaged capillary isoelectric focusing (iCIEF) is a powerful separation technique applied frequently for the analysis of biotherapeutics. However, direct mass spectrometric characterization is usually not possible. Here, focused peaks from an iCIEF system are transferred to a four-port nanoliter valve where peaks of interest are cut and transferred directly (flow injection) or via capillary zone electrophoresis to electrospray mass spectrometry. At first, flow injection coupling was tested with a mixture of peptides showing intraday precision (RSD) of 20...
February 22, 2018: Electrophoresis
Qiong Wang, Cheng-Yu Chung, Sandra Chough, Michael J Betenbaugh
As a key parameter impacting functional and structural heterogeneity, protein glycosylation is a critical quality attribute for antibody biotherapeutic manufacturing. The glycan patterns on recombinant antibodies, particularly on the conserved fragment crystallizable (Fc) region, can have significant effects on an antibody's functional activities including clearance rate, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and anti-inflammatory activity. In this review, we examined specific glycan attachments (fucosylation, sialylation, galactosylation, oligo-mannose and bisecting glycans) and their importance to antibody properties...
February 19, 2018: Biotechnology and Bioengineering
Bowen Li, Zhefan Yuan, Peng Zhang, Andrew Sinclair, Priyesh Jain, Kan Wu, Caroline Tsao, Jingyi Xie, Hsiang-Chieh Hung, Xiaojie Lin, Tao Bai, Shaoyi Jiang
For biotherapeutics that require multiple administrations to fully cure diseases, the induction of undesirable immune response is one common cause for the failure of their treatment. Covalent binding of hydrophilic polymers to proteins is commonly employed to mitigate potential immune responses. However, while this technique is proved to partially reduce the antibodies (Abs) reactive to proteins, it may induce Abs toward their associated polymers and thus result in the loss of efficacy. Zwitterionic poly(carboxybetaine) (PCB) is recently shown to improve the immunologic properties of proteins without inducing any antipolymer Abs against itself...
February 19, 2018: Advanced Materials
Jun Qu
Jun Qu speaks to Sankeetha Nadarajah, Editor of Bioanalysis: Jun Qu is the group leader of the proteomics and pharmaceutical analysis lab of SUNY-Buffalo (NY, USA) and a Professor in the Department of Pharmaceutical Sciences. His research is focused on the study of Clinical and Pharmaceutical Proteomics and Pharmaceutical Analysis using LC-MS-based strategies. His research programs include high-resolution and large-scale expression profiling of pathological proteomes, for the discovery of novel disease/therapeutics biomarkers using gel-free proteomic methods; sensitive identification, localization and quantification of post-translational modifications in tissue proteomes such as these in myocardium, using novel anti-PTM affinity capture and alternating Collision-induced dissociation/Electron transfer dissociation to obtain abundant PTM information; targeted investigation of marker proteins that are of high interests for clinical and pharmaceutical study, using highly sensitive nano-LC/SRM-based methods; and highly sensitive and accurate investigation of the PK of biotherapeutics using LC-MS...
February 16, 2018: Bioanalysis
Steven Novick, Perceval Sondag, Tim Schofield, Kenneth Miller
For biotherapeutics and vaccines, potency is measured in a bioassay which compares the concentration-response curves of a new batch to that of a reference standard. Acceptable accuracy and precision of potency measurement is critical to the manufacturing of these products. These characteristics of a bioassay are typically assessed in a procedure which is carried out with samples spanning the acceptable range for the product. During early development, however, a full validation study such as that which is carried out in late development can be costly as it relates to the likelihood of eventual program success...
February 14, 2018: PDA Journal of Pharmaceutical Science and Technology
James B McGivney, Andrew T Csordas, Faye M Walker, Elizabeth R Bagley, Emily M Gruber, Peter L Mage, Jose Casas-Finet, Margaret A Nakamoto, Michael Eisenstein, Christopher J Larkin, Robert J Strouse, H Tom Soh
Biologic drugs are typically manufactured in mammalian host cells, and it is critical from a drug safety and efficacy perspective to detect and remove host cell proteins (HCPs) during production. This is currently achieved with sets of polyclonal antibodies (pAbs), but these suffer from critical shortcomings because their composition is inherently undefined, and they cannot detect nonimmunogenic HCPs. In this work, we report a high-throughput screening and array-based binding characterization strategy that we employed to generate a set of aptamers that overcomes these limitations to achieve sensitive, broad-spectrum detection of HCPs from the widely used Chinese hamster ovary (CHO) cell line...
February 13, 2018: Analytical Chemistry
Joseph F Cartwright, Karin Anderson, Joseph Longworth, Philip Lobb, David C James
High-fidelity replication of biologic-encoding recombinant DNA sequences by engineered mammalian cell cultures is an essential pre-requisite for the development of stable cell lines for the production of biotherapeutics. However, immortalized mammalian cells characteristically exhibit an increased point mutation frequency compared to mammalian cells in vivo, both across their genomes and at specific loci (hotspots). Thus unforeseen mutations in recombinant DNA sequences can arise and be maintained within producer cell populations...
February 10, 2018: Biotechnology and Bioengineering
Rajat Pandey, Venkata Dasu Veeranki
Biosimilar/Biotherapeutic production is becoming a major area of focus for a big chunk of Biotechnology Industry. Easy licensing and already approved status for clinical use has given it a boost. In the present study, recombinant human interferon gamma was expressed for the first time in Kluyveromyces Lactis (K. lactis) expression system and its expression was optimized by varying growth parameters and carbon source concentration with the aim of increasing recombinant protein production level. Human Interferon gamma gene (IFNG) was cloned in the genomic DNA of K...
February 9, 2018: Preparative Biochemistry & Biotechnology
Yizhou Zhou, Ravali Raju, Christina Alves, Alan Gilbert
Chinese hamster ovary (CHO) cells have been extensively used for industrial production of biotherapeutics. With advances in cell line development and process optimization, production levels of therapeutic proteins using the CHO expression system have increased to beyond 10g per liter scale. These high-titer processes could challenge the secretory capacity of CHO cells, which can result in degradation and aggregation of the protein of interest. This review discusses bottlenecks in the secretory pathway of CHO cells that lead to inefficient secretion and aggregation of proteins, and summarizes current strategies to tackle these bottlenecks...
January 29, 2018: Current Opinion in Biotechnology
Alessia Quatela, Adam M Gilmore, Karen E Steege Gall, Marinella Sandros, Karoly Csatorday, Alex Siemiarczuk, Boqian Ben Yang, Loïc Camenen
We investigate the new simultaneous absorbance-transmission and fluorescence excitation-emission matrix method for rapid and effective characterization of the varying components from a mixture. The absorbance-transmission and fluorescence excitation-emission matrix method uniquely facilitates correction of fluorescence inner-filter effects to yield quantitative fluorescence spectral information that is largely independent of component concentration. This is significant because it allows one to effectively monitor quantitative component changes using multivariate methods and to generate and evaluate spectral libraries...
February 5, 2018: Methods and Applications in Fluorescence
Balaji V Sridhar, John R Janczy, Øyvind Hatlevik, Gabriel Wolfson, Kristi S Anseth, Mark W Tibbitt
Modern medicine, biological research, and clinical diagnostics depend on the reli- able supply and storage of complex biomolecules. However, biomolecules are inherently susceptible to thermal stress and the global distribution of value-added biologics, including vaccines, biotherapeutics, and Research Use Only (RUO) proteins, requires an integrated cold chain from point of manufacture to point of use. To mitigate reliance on the cold chain, formulations have been engineered to protect biologics from thermal stress, including materials-based strategies that impart thermal stability via direct encapsulation of the molecule...
February 2, 2018: Biomacromolecules
Sebastian Spindeldreher, Bernard Maillère, Evelyne Correia, Maxime Tenon, Anette Karle, Philip Jarvis, Frank Kolbinger
INTRODUCTION: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy in the treatment of moderate to severe plaque psoriasis (PsO) and psoriatic arthritis (PsA), demonstrating a rapid onset of action and sustained responses with a favorable safety profile. All biotherapeutics, including monoclonal antibodies (mAbs), can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in loss of response and adverse events such as hypersensitivity reactions...
February 1, 2018: Dermatology and Therapy
Vincent P Mauro
Biotherapeutics are increasingly becoming the mainstay in the treatment of a variety of human conditions, particularly in oncology and hematology. The production of therapeutic antibodies, cytokines, and fusion proteins have markedly accelerated these fields over the past decade and are probably the major contributor to improved patient outcomes. Today, most protein therapeutics are expressed as recombinant proteins in mammalian cell lines. An expression technology commonly used to increase protein levels involves codon optimization...
February 2018: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
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