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formulation mab

Silvia Zucchelli, Laura Patrucco, Francesca Persichetti, Stefano Gustincich, Diego Cotella
Mammalian cells are an indispensable tool for the production of recombinant proteins in contexts where function depends on post-translational modifications. Among them, Chinese Hamster Ovary (CHO) cells are the primary factories for the production of therapeutic proteins, including monoclonal antibodies (MAbs). To improve expression and stability, several methodologies have been adopted, including methods based on media formulation, selective pressure and cell- or vector engineering. This review presents current approaches aimed at improving mammalian cell factories that are based on the enhancement of translation...
2016: Computational and Structural Biotechnology Journal
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
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
Bart W Faber, Stephan Hellwig, Sophie Houard, Nicolas Havelange, Jürgen Drossard, Hubert Mertens, Alexander Croon, Robin Kastilan, Richard Byrne, Nicole van der Werff, Marjolein van der Eijk, Alan W Thomas, Clemens H M Kocken, Edmond J Remarque
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading asexual blood stage vaccine candidate for malaria. In preparation for clinical trials, three Diversity Covering (DiCo) PfAMA1 ectodomain proteins, designed to overcome the intrinsic polymorphism that is present in PfAMA1, were produced under Good Manufacturing Practice (GMP) in Pichia pastoris. Using identical methodology, the 3 strains were cultivated in 70-L scale fed-batch fermentations and PfAMA1-DiCos were purified by two chromatography steps, an ultrafiltration/diafiltration procedure and size exclusion chromatography, resulting in highly pure (>95%) PfAMA1-DiCo1, PfAMA1 DiCo2 and PfAMA1 DiCo3, with final yields of 1...
2016: PloS One
Bin Deng, Cristina Lento, Derek J Wilson
Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways...
October 12, 2016: Analytica Chimica Acta
Matthew R Costa, Justin Pollara, Regina Whitney Edwards, Michael S Seaman, Miroslaw K Gorny, David C Montefiori, Hua-Xin Liao, Guido Ferrari, Shan Lu, Shixia Wang
: HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities...
November 15, 2016: Journal of Virology
Janne Olsen Frenvik, Knut Dyrstad, Solveig Kristensen, Olav B Ryan
Targeted Thorium Conjugates (TTCs) are being explored as a potential future platform for specific tumour targeting pharmaceuticals. In TTCs the alpha emitting radionuclide thorium-227 ((227)Th) with a half-life of 18.697 days is labelled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 ((223)Ra, t1/2 = 11.435 days) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of (223)Ra is administrated to the patient...
September 15, 2016: Drug Development and Industrial Pharmacy
Kim Vigor, John Emerson, Robert Scott, Julia Cheek, Claire Barton, Heather J Bax, Debra H Josephs, Sophia N Karagiannis, James F Spicer, Heike Lentfer
The presence of impurities or contaminants in biological products such as monoclonal antibodies (mAb) could affect efficacy or cause adverse reactions in patients. ICH guidelines (Q6A and Q6B) are in place to regulate the level of impurities within clinical drug products. An impurity less often reported and, therefore, lacking regulatory guideline is beta-glucan. Beta-glucans are polysaccharides of d-glucose monomers linked by (1-3) beta-glycosidic bonds, and are produced by prokaryotic and eukaryotic organisms, including plants...
September 7, 2016: Biotechnology Progress
Priscilla Kheddo, Matthew J Cliff, Shahid Uddin, Christopher F van der Walle, Alexander P Golovanov
Assessing how excipients affect the self-association of monoclonal antibodies (mAbs) requires informative and direct in situ measurements for highly concentrated solutions, without sample dilution or perturbation. This study explores the application of solution nuclear magnetic resonance (NMR) spectroscopy for characterization of typical mAb behavior in formulations containing arginine glutamate. The data show that the analysis of signal intensities in 1D (1)H NMR spectra, when compensated for changes in buffer viscosity, is invaluable for identifying conditions where protein-protein interactions are minimized...
August 11, 2016: MAbs
Gerald Drouillard, Gordon Hayward, Julie Vale, Roshni Dutton
As a critical quality attribute, glycosylation represents an important consideration when analyzing the success of a glycoprotein production process. Though critical, glycosylation is not the only measure of culture success; other factors, including culture size, maintenance, and productivity, are also critical. A new metric was developed to address both product quality, as measured through glycosylation, and product quantity, as measured through product concentration. A monoclonal antibody Chinese hamster ovary cell culture model system was used to assess this metric across various media formulations...
October 2016: Cytotechnology
Baoyue Ding, Wei Zhang, Xin Wu, Jeffrey Wang, Chen Xie, Xuan Huang, Shuyu Zhan, Yongxia Zheng, Yueyan Huang, Ningyin Xu, Xueying Ding, Shen Gao
We combined chemo- and immunotherapies by constructing dual therapeutic function immuno-nanoparticles (NPs) consisting of death receptor 5 monoclonal antibody (DR5 mAb)-conjugated nanoparticles loaded with dacarbazine (DTIC) (DTIC-NPs-DR5 mAb). We determined the in vivo targeting specificity of DTIC-NPs-DR5 mAb by evaluating distribution in tumor-bearing nude mice using a real-time imaging system. Therapeutic efficacy was assessed in terms of its effect on tumor volume, survival time, histomorphology, microvessel density (MVD), and apoptotic index (AI)...
August 2, 2016: Oncotarget
Yuezhi Mao, Paul R Horn, Narbe Mardirossian, Teresa Head-Gordon, Chris-Kriton Skylaris, Martin Head-Gordon
Recently developed density functionals have good accuracy for both thermochemistry (TC) and non-covalent interactions (NC) if very large atomic orbital basis sets are used. To approach the basis set limit with potentially lower computational cost, a new self-consistent field (SCF) scheme is presented that employs minimal adaptive basis (MAB) functions. The MAB functions are optimized on each atomic site by minimizing a surrogate function. High accuracy is obtained by applying a perturbative correction (PC) to the MAB calculation, similar to dual basis approaches...
July 28, 2016: Journal of Chemical Physics
Herb Lutz, Joshua Arias, Yu Zou
High therapeutic dosage requirements and the desire for ease of administration drive the trend to subcutaneous administration using delivery systems such as subcutaneous pumps and prefilled syringes. Because of dosage volume limits, prefilled syringe administration requires higher concentration liquid formulations, limited to about 30 cP or roughly 100-300 g L(-1) for mAb's. Ultrafiltration (UF) processes are routinely used to formulate biological therapeutics. This article considers pressure constraints on the UF process that may limit its ability to achieve high final product concentrations...
July 25, 2016: Biotechnology Progress
Salman Muzammil, John R Mabus, Philip R Cooper, Randall J Brezski, Courtney B Bement, Rob Perkinson, Norman D Huebert, Suzanne Thompson, Dalia Levine, Connie Kliwinski, Dino Bradley, Pamela J Hornby
Although much speculation has surrounded intestinally expressed FcRn as a means for systemic uptake of orally administered immunoglobulin G (IgG), this has not been validated in translational models beyond neonates or in FcRn-expressing cells in vitro. Recently, IgG1 intestinal infusion acutely in anesthetized cynomolgus resulted in detectable serum monoclonal antibody (mAb) levels. In this study, we show that IgG2 has greater protease resistance to intestinal enzymes in vitro and mice in vivo, due to protease resistance in the hinge region...
June 2016: Pharmacology Research & Perspectives
Vishal M Toprani, Sangeeta B Joshi, Lisa A Kueltzo, Richard M Schwartz, C Russell Middaugh, David B Volkin
Adequate protein solubility is an important prerequisite for development, manufacture, and administration of biotherapeutic drug candidates, especially for high-concentration protein formulations. A previously established method for determining the relative apparent solubility (thermodynamic activity) of proteins using polyethylene glycol (PEG) precipitation is adapted for screening and comparing monoclonal antibody (mAb) candidates where only limited quantities (≤1 mg) are available. This micro-PEG assay is used to evaluate various broadly neutralizing mAb candidates to HIV-1 viral spike (gp120 and gp41 glycoproteins)...
August 2016: Journal of Pharmaceutical Sciences
Verena Saller, Constanze Hediger, Julia Matilainen, Ulla Grauschopf, Karoline Bechtold-Peters, Hanns-Christian Mahler, Wolfgang Friess
OBJECTIVES: Peristaltic pumps are increasingly employed during fill & finish operations of a biopharmaceutical drug, due to sensitivity of many biological products to rotary piston pump-related stresses. Yet, possibly also unit operations using peristaltic pumps may shed particulates into the final product due to abrasion from the employed tubing. It was the aim of this study to elucidate the potential influence of particles shed from peristaltic pump tubing on the stability of a drug product...
July 1, 2016: Journal of Pharmacy and Pharmacology
Craig Skinner, Stephanie Patfield, Rowaida Khalil, Qiulian Kong, Xiaohua He
Shiga toxin (Stx) is a major virulence factor of several bacterial pathogens that cause potentially fatal illness, including Escherichia coli and Shigella spp. The continual emergence of new subtypes of Stxs presents challenges for the clinical diagnosis of infections caused by Stx-producing organisms. Here, we report the development of four new monoclonal antibodies (MAbs) against Stx1e, a novel subtype of Stx1 that was produced by an Enterobacter cloacae strain and had limited reactivity with existing anti-Stx1 antibodies...
January 2016: MSphere
Jason Z Huang, Karen Liao, George Wang, Thomas Haby, Mark S Bolgar
Monoclonal antibodies (mAb) are being widely studied for the treatment of cancers and other diseases. The mAb is typically in a solution formulation and administered as an intravenous infusion. Ready-to-use solutions are favored for their clinical convenience but they can potentially suffer from a shorter shelf life due to accelerated rates of some forms of degradation such as oxidation, relative to lyophilized formulations. To improve stability, the chelating agent diethylene triamine pentaacetic acid (DTPA) is often used at very low concentrations in biologics formulations to prevent oxidation induced by metal ions...
July 15, 2016: Journal of Chromatography. A
Cor H J Lamers, Yarne Klaver, Jan W Gratama, Stefan Sleijfer, Reno Debets
We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment...
June 15, 2016: Biochemical Society Transactions
Jisheng Lin, Mark A Smith, William H Benjamin, Robert W Kaminski, Heather Wenzel, Moon H Nahm
There is a significant need for an effective multivalent Shigella vaccine that targets the most prevalent serotypes. Most Shigella vaccines under development utilize serotype-specific lipopolysaccharides (LPSs) as a major component based on protection and epidemiological data. As vaccine formulations advance from monovalent to multivalent, assays and reagents need to be developed to accurately and reproducibly quantitate the amount of LPSs from multiple serotypes in the final product. To facilitate this effort, we produced 36 hybridomas that secrete monoclonal antibodies (MAbs) against the O antigen on the LPS from Shigella flexneri 2a, Shigella flexneri 3a, and Shigella sonnei We used six of these monoclonal antibodies for an inhibition enzyme-linked immunosorbent assay (iELISA), measuring LPSs with high sensitivity and specificity...
August 2016: Clinical and Vaccine Immunology: CVI
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