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https://www.readbyqxmd.com/read/28776673/molecular-characterization-of-excipients-preferential-interactions-with-therapeutic-monoclonal-antibodies
#1
Jehoon Kim, Mark R H Krebs, Bernhardt L Trout
OBJECTIVES: This study reports global and local monoclonal antibody (mAb)-excipient interactions and the resulting thermodynamic and stabilization effects. METHODS: Molecular dynamics simulations are applied to quantify the interactions of key excipients (sucrose, sorbitol, arginine, citrate, histidine and NaCl) used in the formulations of three mAbs. The dynamic surface properties of the mAbs and preferential interaction coefficients for the excipients based on validated potential parameters are computed, in addition to the spatial aggregation propensity...
August 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28774565/immunocapture-isotope-dilution-mass-spectrometry-in-response-to-a-pandemic-influenza-threat
#2
Carrie L Pierce, Tracie L Williams, Wanda I Santana, Marnie Levine, Li-Mei Chen, Hans C Cooper, Maria I Solano, Adrian R Woolfitt, Wayne A Marasco, He Fang, Ruben O Donis, John R Barr
As a result of recent advances in mass spectrometry-based protein quantitation methods, these techniques are now poised to play a critical role in rapid formulation of pandemic influenza vaccines. Analytical techniques that have been developed and validated on seasonal influenza strains can be used to increase the quality and decrease the time required to deliver protective pandemic vaccines to the global population. The emergence of a potentially pandemic avian influenza A (H7N9) virus in March of 2013, prompted the US public health authorities and the vaccine industry to initiate production of a pre-pandemic vaccine for preparedness purposes...
July 31, 2017: Vaccine
https://www.readbyqxmd.com/read/28758834/preferential-interactions-of-trehalose-l-arginine-hcl-and-sodium-chloride-with-therapeutically-relevant-igg1-monoclonal-antibodies
#3
Chaitanya Sudrik, Theresa Cloutier, Phuong Pham, Hardeep S Samra, Bernhardt L Trout
Preferential interactions of weakly interacting formulation excipients govern their effect on the equilibrium and kinetics of several reactions of protein molecules in solution. Using vapor pressure osmometry, we characterized the preferential interactions of commonly used excipients trehalose, L-arginine.HCl and NaCl with three therapeutically-relevant, IgG1 monoclonal antibodies that have similar size and shape, but differ in their surface hydrophobicity and net charge. We further characterized the effect of these excipients on the reversible self-association, aggregation and viscosity behavior of these antibody molecules...
July 31, 2017: MAbs
https://www.readbyqxmd.com/read/28754261/elucidating-the-weak-protein-protein-interaction-mechanisms-behind-the-liquid-liquid-phase-separation-of-a-mab-solution-by-different-types-of-additives
#4
Guoliang Wu, Shujing Wang Co-First, Zhou Tian, Ning Zhang, Han Sheng, Weiguo Dai, Feng Qian
Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering...
July 25, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28753295/empirical-correction-for-differences-in-chemical-exchange-rates-in-hydrogen-exchange-mass-spectrometry-measurements
#5
Ronald T Toth, Brittney J Mills, Sangeeta B Joshi, Reza Esfandiary, Steven M Bishop, C Russell Middaugh, David B Volkin, David D Weis
A barrier to the use of hydrogen exchange-mass spectrometry (HX-MS) in many contexts, especially analytical characterization of various protein therapeutic candidates, is that differences in temperature, pH, ionic strength, buffering agent, or other additives can alter chemical exchange rates, making HX data gathered under differing solution conditions difficult to compare. Here, we present data demonstrating that HX chemical exchange rates can be substantially altered not only by the well-established variables of temperature and pH but also by additives including arginine, guanidine, methionine, and thiocyanate...
August 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28690199/high-concentration-protein-formulations-how-high-is-high
#6
Patrick Garidel, Alexander B Kuhn, Lars V Schäfer, Anne R Karow-Zwick, Michaela Blech
High-concentration protein formulation (HCPF) is a term that is used to describe protein formulations, mostly monoclonal antibody (mAb) drugs, at high protein concentration. The concentration is rarely defined, with typical ranges varying between 50 and 150 mg/ml for mAbs. The term HCPF is meant to include and express specific solution properties of formulations that are prone to appear at high protein concentrations such as high viscosity, high opalescence, phase separation, gel formation or the increased propensity for protein particle formation...
July 6, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28668340/a-formulation-development-approach-to-identify-and-select-stable-ultra-high-concentration-monoclonal-antibody-formulations-with-reduced-viscosities
#7
Neal Whitaker, Jian Xiong, Samantha E Pace, Vineet Kumar, C Russell Middaugh, Sangeeta B Joshi, David B Volkin
High protein concentration formulations are required for low volume administration of therapeutic antibodies targeted for subcutaneous, self-administration by patients. Ultra-high concentrations (≥ 150 mg/mL) can lead to dramatically increased solution viscosities, which in turn can lead to stability, manufacturing and delivery challenges. In this study, various categories and individual types of pharmaceutical excipients and other additives (58 in total) were screened for their viscosity reducing effects on two different monoclonal antibodies (mAbs)...
June 28, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28617076/characterization-of-highly-concentrated-antibody-solution-a-toolbox-for-the-description-of-protein-long-term-solution-stability
#8
Marie-Therese Schermeyer, Anna K Wöll, Bas Kokke, Michel Eppink, Jürgen Hubbuch
High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long-term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations...
June 15, 2017: MAbs
https://www.readbyqxmd.com/read/28614662/investigating-liquid-liquid-phase-separation-of-a-monoclonal-antibody-using-solution-state-nmr-spectroscopy-effect-of-arg%C3%A2-glu-and-arg%C3%A2-hcl
#9
Priscilla Kheddo, Jack E Bramham, Rebecca J Dearman, Shahid Uddin, Christopher F van der Walle, Alexander P Golovanov
Liquid-liquid phase separation (LLPS) of monoclonal antibody (mAb) formulations involves spontaneous separation into dense (protein-rich) and diluted (protein-lean) phases and should be avoided in the final drug product. Understanding the factors leading to LLPS and ways to predict and prevent it would therefore be highly beneficial. Here we describe the link between LLPS behavior of an IgG1 mAb (mAb5), its solubility, and parameters extracted using (1)H NMR spectroscopy, for various formulations. We show that the formulations demonstrating least LLPS lead to the largest mAb5 NMR signal intensities...
August 7, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28593474/high-throughput-prediction-approach-for-monoclonal-antibody-aggregation-at-high-concentration
#10
Mitja Zidar, Ana Šušterič, Miha Ravnik, Drago Kuzman
PURPOSE: Characterization of the monoclonal antibody aggregation process and identification of stability factors that could be used as indicators of aggregation propensity with an emphasis on a large number of samples and low protein material consumption. METHODS: Differential scanning calorimetry, dynamic light scattering and size exclusion chromatography were used as the main methodological approaches. Conformational stability, colloidal stability and aggregation kinetics were assessed for two different IgG monoclonal antibody (mAbs) subclasses...
September 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28570837/high-throughput-screening-and-analysis-of-charge-variants-of-monoclonal-antibodies-in-multiple-formulations
#11
Larysa Alekseychyk, Cheng Su, Gerald W Becker, Michael J Treuheit, Vladimir I Razinkov
Among different biopharmaceutical products, monoclonal antibodies (mAbs) show a high level of complexity, including heterogeneity due to differences in size, hydrophobicity, charge, and so forth. Such heterogeneity can be related to both cell-based production and any of the stages of purification, storage, and delivery that the mAb is subjected to. Choosing the right formulation composition providing both physical and chemical stabilities can be a very challenging process, especially when done in the limited time frame required for a typical drug development cycle...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28502677/biophysical-study-of-bevacizumab-structure-and-bioactivity-under-thermal-and-ph-stresses
#12
Flávia Sousa, Bruno Sarmento, Maria Teresa Neves-Petersen
The evaluation of the structural stability and bioactivity of monoclonal antibodies (mAb) is a crucial step in the development of mAb therapeutic based products, since immunogenicity needs to be avoided. In the present work, a study was carried out to understand the changes on the structure and bioactivity of mAbs induced by different pH and temperature values. Structural changes of bevacizumab were monitored using fluorescence spectroscopy, circular dichroism (CD) and Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR)...
May 11, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28495581/dipicolinic-acid-as-a-novel-spore-inspired-excipient-for-antibody-formulation
#13
Iris L Batalha, Peng Ke, Esther Tejeda-Montes, Shahid Uddin, Christopher F van der Walle, Graham Christie
Ionic excipients are commonly used in aqueous therapeutic monoclonal antibody (mAb) formulations. Novel excipients are of industrial interest, with a recent focus on Arg salt forms and their application as viscosity reducing and stabilizing additives. Here, we report that the calcium salt of dipicolinic acid (DPA, pyridine-2,6-dicarboxylic acid), uniquely present in nature in the core of certain bacterial spores, reduces the viscosity of a mAb formulated at 150mg/mL, below that achieved by Arg hydrochloride at the same concentration (10mM)...
May 8, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28486309/rationale-for-therapeutic-drug-monitoring-of-biopharmaceuticals-in-inflammatory-diseases
#14
Gilles Paintaud, Christophe Passot, David Ternant, Antonio Bertolotto, Theodora Bejan-Angoulvant, Dora Pascual-Salcedo, Denis Mulleman
Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to "chemical" drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability...
August 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28479354/lyophilization-cycle-design-for-dual-chamber-cartridges-and-a-method-for-online-process-control-the-dcc-lyomate-procedure
#15
Christoph Korpus, Wolfgang Friess
Freeze-drying process design is a challenging task that necessitates a profound understanding of the complex interrelation among critical process parameters (e.g., shelf temperature and chamber pressure), heat transfer characteristics of the involved materials (e.g., product containers and holder devices), and critical quality attributes of the product (e.g., collapse temperatures). The Dual Chamber Cartridge "(DCC) LyoMate" (from lyophilization and automated) is a manometric temperature measurement-based process control strategy that was developed within this study to streamline this complicated task...
August 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28464237/ultrafiltration-behavior-of-monoclonal-antibodies-and-fc-fusion-proteins-effects-of-physical-properties
#16
Youngbin Baek, Nripen Singh, Abhiram Arunkumar, Michael Borys, Zheng J Li, Andrew L Zydney
Ultrafiltration (UF) is used for the final concentration and formulation of essentially all antibody-based therapeutics including both monoclonal antibodies (mAbs) and Fc-fusion proteins. The objective of this study was to quantitatively compare the filtrate flux behavior for two highly purified mAbs and an Fc-fusion protein under identical flow and buffer conditions. Filtrate flux data were obtained using a Pellicon 3 tangential flow filtration cassette over a wide range of transmembrane pressures and bulk protein concentrations...
September 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28464235/multi-criteria-manufacturability-indices-for-ranking-high-concentration-monoclonal-antibody-formulations
#17
Yang Yang, Ajoy Velayudhan, Nina F Thornhill, Suzanne S Farid
The need for high-concentration formulations for subcutaneous delivery of therapeutic monoclonal antibodies (mAbs) can present manufacturability challenges for the final ultrafiltration/diafiltration (UF/DF) step. Viscosity levels and the propensity to aggregate are key considerations for high-concentration formulations. This work presents novel frameworks for deriving a set of manufacturability indices related to viscosity and thermostability to rank high-concentration mAb formulation conditions in terms of their ease of manufacture...
September 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28421387/pharmacokinetics-of-monoclonal-antibodies-and-fc-fusion-proteins
#18
REVIEW
Liming Liu
There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life...
April 19, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28402743/generation-and-application-of-monoclonal-antibody-against-lycopene
#19
Valeriy V Tsibezov, Yuriy K Bashmakov, Dmitry V Pristenskiy, Naylia A Zigangirova, Ludmila V Kostina, Natalya E Chalyk, Alexey Y Kozlov, Elena Y Morgunova, Marina P Chernyshova, Marina V Lozbiakova, Nigel H Kyle, Ivan M Petyaev
A monoclonal antibody (Mab) against lycopene was developed from hybridoma clones obtained from BALB/c mice immunized with trans-isomer of lycopene (t-lycopene, t-LC) conjugated with colloidal gold particles. An alternating immunization schedule which included injection of both formulations of immunogen (without and with Freund's adjuvant) was most effective in the elucidation of a measurable immune response to the t-Lycopene conjugate. Selected hybridoma clones were able to produce an Mab positive in competition assay...
April 12, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28400066/development-of-a-fast-workflow-to-screen-the-charge-variants-of-therapeutic-antibodies
#20
Elsa Wagner-Rousset, Szabolcs Fekete, Laura Morel-Chevillet, Olivier Colas, Nathalie Corvaïa, Sarah Cianférani, Davy Guillarme, Alain Beck
Chemical or enzymatic modifications of therapeutic monoclonal antibodies (mAbs) having high risk towards safety and efficacy are defined as critical quality attributes (CQAs). During therapeutic mAbs process development, a variety of analytical techniques have to be used for the thorough characterization and quantitative monitoring of CQAs. This paper describes the development of a rapid analytical platform to assess and rank charge variants of mAbs. The workflow is first based on a cation exchange chromatography (CEX) comparative analysis of intact IgGs versus F(ab)'2 and Fc sub-domains generated by IdeS digestion...
February 27, 2017: Journal of Chromatography. A
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