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https://www.readbyqxmd.com/read/29135256/improved-solution-state-properties-of-monoclonal-antibodies-by-targeted-mutations
#1
Alexander B Kuhn, Sebastian Kube, Anne R Karow-Zwick, Daniel Seeliger, Patrick Garidel, Michaela Blech, Lars V Schäfer
Monoclonal antibody (mAb) based therapeutics often require high concentration formulations. Unfortunately, highly concentrated antibody solutions often have biophysical properties that are disadvantageous for therapeutic development, such as high viscosity, solubility limitations, precipitation issues, or liquid-liquid phase separation. In this work, we present a computational rational design principle for improving the thermodynamic stability of mAb solutions through targeted point mutations. Two publicly available IgG1 monoclonal antibodies that exhibit high viscosity at high concentrations were used as model systems...
November 14, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29101419/fully-disposable-manufacturing-concepts-for-clinical-and-commercial-manufacturing-and-ballroom-concepts
#2
Berthold Boedeker, Adam Goldstein, Ekta Mahajan
The availability and use of pre-sterilized disposables has greatly changed the methods used in biopharmaceuticals development and production, particularly from mammalian cell culture. Nowadays, almost all process steps from cell expansion, fermentation, cell removal, and purification to formulation and storage of drug substances can be carried out in disposables, although there are still limitations with single-use technologies, particularly in the areas of pretesting and quality control of disposables, bag and connections standardization and qualification, extractables and leachables (E/L) validation, and dependency on individual vendors...
November 4, 2017: Advances in Biochemical Engineering/biotechnology
https://www.readbyqxmd.com/read/29067591/nanoparticulate-impurities-isolated-from-pharmaceutical-grade-sucrose-are-a-potential-threat-to-protein-stability
#3
Daniel Weinbuch, Mitchel Ruigrok, Wim Jiskoot, Andrea Hawe
PURPOSE: To investigate the effect of nanoparticulate impurities (NPIs) isolated from pharmaceutical-grade sucrose, on the stability of monoclonal antibodies (mAbs). METHODS: NPIs were purified from pharmaceutical-grade sucrose and spiked into trastuzumab, rituximab, infliximab, and cetuximab formulations. The stability of the mAbs as a function of storage time, temperature, and NPI concentration was assessed by visual inspection, flow-imaging microscopy, nanoparticle tracking analysis, size-exclusion chromatography, capillary isoelectric focusing, and intrinsic differential scanning fluorimetry...
October 24, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/29056527/flow-cytometry-an-efficient-method-for-antigenicity-measurement-and-particle-characterization-on-an-adjuvanted-vaccine-candidate-h4-ic31-for-tuberculosis
#4
Liwei He, Jin Su, Marin Ming, Lidice Bernardo, Tricia Chen, Lucy Gisonni-Lex, Beata Gajewska
We have developed an accurate, precise and stability-indicating flow cytometry (FC) based assay to directly measure antigenicity of H4 protein (also known as HyVac4) in a vaccine formulation of H4-IC31, without desorbing the H4 protein from the IC31 adjuvant. This method involves immuno-staining of H4-IC31 complex with anti-H4 monoclonal antibodies (mAbs) followed by FC analysis. The assay is not only able to consistently measure H4 antigenicity levels in H4-IC31 stored under normal condition at 2-8°C, but also able to detect changes in H4 antigenicity after H4-IC31 undergoes heat stress or freeze-thawing...
October 19, 2017: Journal of Immunological Methods
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
#5
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
https://www.readbyqxmd.com/read/29030532/mechanistic-investigation-on-grinding-induced-subvisible-particle-formation-during-mixing-and-filling-of-monoclonal-antibody-formulations
#6
Benson Gikanga, Ada Hui, Yuh-Fun Maa
Processing equipment involving grinding of two solid surfaces has been demonstrated to induce subvisible particle (SvP) formation in monoclonal antibody (mAb) drug product manufacturing processes. This study elucidated potential stress types associated with grinding action to identify the stress mechanism responsible for SvP formation. Several potential stress types can be associated with the grinding action, including interfacial stresses (air-liquid and liquid-solid), hydraulic/mechanical shear stress, cavitation, nucleation of stressed protein molecules, and localized thermal stress...
October 12, 2017: PDA Journal of Pharmaceutical Science and Technology
https://www.readbyqxmd.com/read/28989015/the-use-of-a-2-2-azobis-2-amidinopropane-dihydrochloride-aaph-stress-model-as-an-indicator-of-oxidation-susceptibility-for-monoclonal-antibodies
#7
Michelle Z Dion, Y John Wang, Daniel Bregante, Wayman Chan, Nisana Andersen, Amy Hilderbrand, Danielle Leiske, Cleo M Salisbury
Protein oxidation is a major pathway for degradation of biologic drug products. Past literature reports have suggested that AAPH, a free radical generator that produces alkoxyl and alkyl peroxyl radicals, is a useful model reagent stress for assessing the oxidative susceptibility of proteins. Here, we expand the applications of the AAPH model by pairing it with a rapid peptide map method to enable site-specific studies of oxidative susceptibility of monoclonal antibodies (mAbs) and their derivatives for comparison between formats, the evaluation of formulation components, and comparisons across stress models...
October 5, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28978341/mab-mdr1-modified-chitosan-nanoparticles-overcome-acquired-egfr-tki-resistance-through-two-potential-therapeutic-targets-modulation-of-mdr1-and-autophagy
#8
Yan Zheng, Chang Su, Liang Zhao, Yijie Shi
BACKGROUND: Tyrosine kinase inhibitors (TKIs) that act against the epithelial growth factor receptor (EGFR) were once widely used in chemotherapy for many human cancers. However, acquired chemoresistance occurred in almost all patients, limiting the clinical application of EGFR-TKI. Thus far, no effective methods existing can resolve this problem. Designing a therapeutic treatment with a specific multi-target profile has been regarded as a possible strategy to overcome acquired EGFR-TKI resistance...
October 4, 2017: Journal of Nanobiotechnology
https://www.readbyqxmd.com/read/28921443/polyester-based-nanoparticles-for-the-encapsulation-of-monoclonal-antibodies
#9
Flávia Sousa, Pedro Fonte, Andreia Cruz, Patrick J Kennedy, Inês Mendes Pinto, Bruno Sarmento
Aliphatic polyesters have been widely explored for biomedical applications (e.g., drug delivery systems, biomedical devices, and tissue engineering). Recently, polyesters have been used in nanoparticle formulations for the controlled release of monoclonal antibodies (mAbs) for the enhanced efficacy of antibody-based therapy. Polyester-based nanoparticles for mAb delivery provide decreased antibody dosage, increased antibody stability and protection and longer therapeutic action, ultimately translating to an increased therapeutic index...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28880521/peptide-dendrons-as-thermal-stability-amplifiers-for-immunoglobulin-g1-monoclonal-antibody-biotherapeutics
#10
Rohit Bansal, Sameer Dhawan, Soumili Chattopadhyay, Govind P Maurya, V Haridas, Anurag S Rathore
Biotherapeutics such as monoclonal antibodies (mAbs) have a major share of the pharmaceutical industry for treatment of life-threatening chronic diseases such as cancer, skin ailments, and immune disorders. Instabilities such as aggregation, fragmentation, oxidation, and reduction have resulted in the practice of storing these products at low temperatures (-80 to -20 °C). However, reliable storage at these temperatures can be a challenge, particularly in developing and underdeveloped countries; hence, lately, there has been a renewed interest in creating formulations that would offer stability at higher temperatures (25 to 55 °C)...
October 18, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28843351/effect-of-polysorbate-20-and-polysorbate-80-on-the-higher-order-structure-of-a-monoclonal-antibody-and-its-fab-and-fc-fragments-probed-using-2d-nuclear-magnetic-resonance-spectroscopy
#11
Surinder M Singh, Swati Bandi, David N M Jones, Krishna M G Mallela
We examined how polysorbate 20 (PS20; Tween 20) and polysorbate 80 (PS80; Tween 80) affect the higher-order structure of a monoclonal antibody (mAb) and its antigen-binding (Fab) and crystallizable (Fc) fragments, using near-UV circular dichroism and 2D nuclear magnetic resonance (NMR). Both polysorbates bind to the mAb with submillimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure. 2D (13)C-(1)H methyl NMR indicates that with increasing concentration of polysorbates, the Fab region showed a decrease in crosspeak volumes...
August 24, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28822152/-preparation-of-cd123-mono-antibody-modified-tanshinone-%C3%A2-a-loaded-immunoliposome-and-its-in-vitro-evaluation
#12
Yin Wang, Fu-Rong Liu, Hong-Lin Xiang, Hong Qing, Chen Chen, Sheng-Jun Mao, Hui Li
In the study, we developed a novel formulation, CD123 mono-antibody (mAb) modified tanshinone ⅡA loaded immunoliposome (CD123-TanⅡA-ILP) to achieve the targeted drug delivery for leukemia cells. Orthogonal test was used to optimize liposome preparation, and the TanⅡA-loaded PEGylated liposomes (TanⅡA-LP) of S100PC-Chol-(mPEG2000-DSPE)-TanⅡA at 19∶5∶1∶1 molar ratio were prepared by the thin film hydration-probe ultrasonic method. A post-insertion method was applied to prepare CD123-TanⅡA-ILP via thiolated mAb conjugated to the terminal of maleimide-PEG2000-DSPE...
June 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28776673/molecular-characterization-of-excipients-preferential-interactions-with-therapeutic-monoclonal-antibodies
#13
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
#14
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
#15
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...
October 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
#16
Guoliang Wu, Shujing Wang, 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...
November 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
#17
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...
September 5, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28690199/high-concentration-protein-formulations-how-high-is-high
#18
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 150mg/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...
October 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
#19
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 (56 in total) were screened for their viscosity reducing effects on 2 different 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
#20
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...
October 2017: MAbs
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