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https://www.readbyqxmd.com/read/29761239/kinetics-and-characterization-of-non-enzymatic-fragmentation-of-monoclonal-antibody-therapeutics
#1
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
https://www.readbyqxmd.com/read/29746518/an-ambient-temperature-stable-antitoxin-of-nine-co-formulated-antibodies-for-botulism-caused-by-serotypes-a-b-and-e
#2
Mingxiang Li, Dennis Lee, Chidi R Obi, Joel K Freeberg, Shauna Farr-Jones, Milan T Tomic
Safe and effective antitoxins to treat and prevent botulism are needed for biodefense. We have developed recombinant antibody-based therapeutics for botulinum neurotoxin (BoNT) serotypes A, B, and E. The mechanism of action of this antitoxin requires that three mAbs bind one toxin molecule to achieve clearance. Here we present a co-formulation of an antitoxin to the three most important serotypes. Combining these antibodies obviates the need to identify the serotype causing intoxication prior to drug administration, which would facilitate administration...
2018: PloS One
https://www.readbyqxmd.com/read/29724643/adsorption-of-polysorbate-20-and-proteins-on-hydrophobic-polystyrene-surfaces-studied-by-neutron-reflectometry
#3
Zhenhuan Zhang, Sara Orski, Ann Marie Woys, Guangcui Yuan, Isidro E Zarraga, Norman J Wagner, Yun Liu
Understanding the adsorption of protein and surfactant molecules on hydrophobic surfaces is very important for storage stability and delivery of pharmaceutical liquid formulations as many commonly-used devices, such as drug containers and syringes, have hydrophobic surfaces. Neutron reflectometry is used here to investigate the structure information of the adsorption process of non-ionic surfactant (polysorbate 20) and proteins (monoclonal antibody (mAb) and lysozyme) on polystyrene surfaces. Thickness of adsorbed polysorbate 20 thin film is observed to be ≈21 Å, comparable to the radius of gyration of polysorbate 20 micelles in solution...
April 21, 2018: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/29723667/the-missing-piece-in-the-puzzle-prediction-of-aggregation-via-the-protein-protein-interaction-parameter-a-%C3%A2-2
#4
Ellen Koepf, Rudolf Schroeder, Gerald Brezesinski, Wolfgang Friess
The tendency of protein pharmaceuticals to form aggregates is a major challenge during formulation development, as aggregation affects quality and safety of the product. In particular, the formation of large native-like particles in the context of liquid-air interfacial stress is a well-known but not fully understood problem. Focusing on the two most fundamental criteria of protein formulation affecting protein-protein interaction, the impact of pH and ionic strength on the interaction parameter A∗ 2 and its link to aggregation upon mechanical stress was investigated...
April 30, 2018: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29713822/improving-viscosity-and-stability-of-a-highly-concentrated-monoclonal-antibody-solution-with-concentrated-proline
#5
Jessica J Hung, Barton J Dear, Aileen K Dinin, Ameya U Borwankar, Sumarth K Mehta, Thomas T Truskett, Keith P Johnston
PURPOSE: To explain the effects of the osmolyte proline on the protein-protein interactions (PPI), viscosity and stability of highly concentrated antibody solutions in contrast to other neutral osmolytes. METHODS: The viscosity of ~225 mg/mL mAb solutions was measured with proline, glycine and trehalose as a function of pH and co-solute concentration up to 1.3 M. The stability was assessed via turbidity as well as size exclusion chromatography after 4 weeks storage at 40°C...
April 30, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29708899/the-return-of-pro-140-a-ccr5-directed-mab
#6
Melanie A Thompson
PURPOSE OF REVIEW: Although antiretroviral therapy has become more potent and tolerable, adherence remains a barrier to continuous viral suppression and new approaches are needed. PRO 140 is a C-C chemokine receptor 5 (CCR5)-directed mAb with potential for weekly subcutaneous dosing. This review discusses data from the PRO 140 clinical development program including emerging data from ongoing efficacy studies. RECENT FINDINGS: Phase II development of PRO 140 began over a decade ago, and recently initiated phase IIb and III trials are ongoing in study participants with virologic failure and as monotherapy maintenance in virologically suppressed study participants...
April 27, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29663323/single-pass-diafiltration-integrated-into-a-fully-continuous-mab-purification-process
#7
Joanna Rucker-Pezzini, Lindsay Arnold, Kevin Hill-Byrne, Tom Sharp, Maksim Avazhanskiy, Chris Forespring
The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published...
April 16, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29644623/single-pass-diafiltration-integrated-into-a-fully-continuous-mab-purification-process
#8
Joanna Rucker-Pezzini, Lindsay Arnold, Kevin Hill-Byrne, Tom Sharp, Maksim Avazhanskiy, Chris Forespring
The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published...
April 12, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29626535/biophysical-properties-and-heating-induced-aggregation-of-lysine-conjugated-antibody-drug-conjugates
#9
Aditya V Gandhi, Keith J Arlotta, Hsiao-Nung Chen, Shawn C Owen, John F Carpenter
The commercially available antibody-drug conjugate (ADC) product, Kadcyla® is synthesized using a two-step reaction, wherein the linker is conjugated to native lysines on the monoclonal antibody (mAb) in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine conjugated ADC (Syn-ADC) on the same trastuzumab scaffold as Kadcyla® using a one-step reaction. Mass spectrometry of both products revealed a sub-population of Kadcyla® containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the one-step reaction ADC product...
April 4, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29623520/cgrp-monoclonal-antibodies-for-the-preventative-treatment-of-migraine
#10
REVIEW
Heike Israel, Lars Neeb, Uwe Reuter
PURPOSE OF REVIEW: CGRP is a key neuropeptide in migraine pathophysiology. The blockade of the CGRP pathway at the side of the CGRP receptor of the CGRP peptide leads to the interruption of trigeminal nerve system-mediated headache syndromes such as migraine. Monoclonal antibodies (mAbs) targeting the CGRP pathway have been developed and are currently under investigation for episodic (EM) and chronic migraine (CM) prevention. Here, we report data from these clinical trials. RECENT FINDINGS: Placebo-controlled, randomized double-blind phase studies of CGRP mAbs in episodic and chronic migraine have shown that the specific blockade of the peptide or the CGRP receptor are both powerful mechanisms to reduce migraine frequency...
April 6, 2018: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/29611470/polymeric-immunonanoparticles-mediated-cancer-therapy-versatile-nanocarriers-for-cell-specific-cargo-delivery
#11
Namdev L Dhas, Ritu R Kudarha, Niyati S Acharya, Sanjeev R Acharya
The major drawback with conventional therapeutic approaches for cancer therapy is decreased efficacy and redundant therapy associated toxicity and side effects causing increased patient discomfort. With the aim of minimizing these limitations, a vast amount of attention has been given to targeted nanocarrier-based drug delivery systems that possess a several-fold advantage over conventional therapy. Increased research in targeted nanoparticulate systems has led to the development of immunonanoparticles with enhanced efficacy and targeting efficiency along with decreased drug-resistant cancer- and dose-related toxicity...
2018: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/29600470/photokinetic-drug-delivery-near-infrared-nir-induced-permeation-enhancement-of-bevacizumab-ranibizumab-and-aflibercept-through-human-sclera
#12
Steven A Giannos, Edward R Kraft, Zhen-Yang Zhao, Kevin H Merkley, Jiyang Cai
PURPOSE: Permeation studies, with near infrared (NIR) light and anti-aggregation antibody formulation, were used to investigate the in vitro permeation of bevacizumab, ranibizumab and aflibercept through human sclera. METHODS: A vertical, spherical Franz cell diffusion apparatus was used for this scleral tissue permeation model. A photokinetic ocular drug delivery (PODD) testing device accommodated the placement of NIR LEDs above the donor chambers. An adjustable LED driver/square wave generator provided electrical energy with a variable pulse rate and pulse width modulation (duty cycle)...
March 29, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29571738/determination-of-interaction-parameters-for-reversibly-self-associating-antibodies-a-comparative-analysis
#13
Mandi M Hopkins, Cherie M Lambert, Jared S Bee, Arun Parupudi, David L Bain
Monoclonal antibodies (mAbs) represent a major class of biotherapeutics, and are the fastest growing category of biologic drugs on the market. However, mAb development and formulation are often impeded by reversible self-association (RSA), defined as the dynamic exchange of monomers with native-state oligomers. Here we present a comparative analysis of the self-association properties for five IgG mAbs, under matched conditions and using orthogonal methods. Concentration-dependent dynamic light scattering and sedimentation velocity studies revealed that the majority of mAbs examined exhibited weak to moderate RSA...
March 20, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29556730/impact-of-buffer-protein-concentration-and-sucrose-addition-on-the-aggregation-and-particle-formation-during-freezing-and-thawing
#14
Astrid Hauptmann, Katja Podgoršek, Drago Kuzman, Stanko Srčič, Georg Hoelzl, Thomas Loerting
PURPOSE: This study addresses the effect of freezing and thawing on a therapeutic monoclonal antibody (mAb) solution and the corresponding buffer formulation. Particle formation, crystallization behaviour, morphology changes and cryo-concentration effects were studied after varying the freezing and thawing rates, buffer formulation and protein concentration. The impact of undergoing multiple freeze/thaw (FT)-cycles at controlled and uncontrolled temperature rates on mAb solutions was investigated in terms of particle formation...
March 19, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29499299/formulating-monoclonal-antibodies-as-powders-for-reconstitution-at-high-concentration-using-spray-drying-models-and-pitfalls
#15
Maarten Batens, Jan Massant, Bianca Teodorescu, Guy Van den Mooter
In anticipation of non-invasive routes capable of delivering adequately high, systemic monoclonal antibody (mAb) concentrations, subcutaneous (SC) injection is arguably the most patient friendly alternative administration route available for this drug class. However, due to the limited volume that can be administered through this route and mAbs' relatively low therapeutic activity, solutions for subcutaneous injection often need to be highly concentrated, making them inherently more prone to potentially detrimental protein (self-) interaction, which is why mAb formulations for SC injection and other highly concentrated mAb solutions are often dried to increase their stability...
June 2018: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29492680/formulation-stabilization-and-disaggregation-of-bevacizumab-ranibizumab-and-aflibercept-in-dilute-solutions
#16
Steven A Giannos, Edward R Kraft, Zhen-Yang Zhao, Kevin H Merkley, Jiyang Cai
PURPOSE: Studies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use in in vitro permeation studies. METHODS: Excipient substitutions were screened. The most stabilizing formulation was chosen. Standard dilutions of bevacizumab, ranibizumab and aflibercept were prepared in PBS, manufacturer's formulation, and the new formulation...
February 28, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29448116/immunoliposomes-in-clinical-oncology-state-of-the-art-and-future-perspectives
#17
REVIEW
María Merino, Sara Zalba, María J Garrido
Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab', to the polymers covering the surface of liposomes...
April 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29425047/protein-adsorption-and-layer-formation-at-the-stainless-steel-solution-interface-mediates-shear-induced-particle-formation-for-an-igg1-monoclonal-antibody
#18
Cavan K Kalonia, Frank Heinrich, Joseph E Curtis, Sid Raman, Maria A Miller, Steven D Hudson
Passage of specific protein solutions through certain pumps, tubing, and/or filling nozzles can result in the production of unwanted subvisible protein particles (SVPs). In this work, surface-mediated SVP formation was investigated. Specifically, the effects of different solid interface materials, interfacial shear rates, and protein concentrations on SVP formation were measured for the National Institute of Standards and Technology monoclonal antibody (NISTmAb), a reference IgG1 monoclonal antibody (mAb). A stainless steel rotary piston pump was used to identify formulation and process parameters that affect aggregation, and a flow cell (alumina or stainless steel interface) was used to further investigate the effect of different interface materials and/or interfacial shear rates...
March 5, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29355621/in-vitro-model-for-predicting-bioavailability-of-subcutaneously-injected-monoclonal-antibodies
#19
Hanne Kinnunen Bown, Catherine Bonn, Stefan Yohe, Daniela Bumbaca Yadav, Thomas W Patapoff, Ann Daugherty, Randall J Mrsny
Monoclonal antibodies (mAbs), which are now more frequently administered by subcutaneous (SC) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. Preclinical evaluations of mAbs to be administered by SC injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of PK/PD outcomes needed to select clinical doses for first-in-human studies...
March 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29355022/probing-the-conformation-of-an-igg1-monoclonal-antibody-in-lyophilized-solids-using-solid-state-hydrogen-deuterium-exchange-with-mass-spectrometric-analysis-sshdx-ms
#20
Ehab M Moussa, Satish K Singh, Michael Kimmel, Sandeep Nema, Elizabeth M Topp
Therapeutic proteins are often formulated as lyophilized products to improve their stability and prolong shelf life. The stability of proteins in the solid-state has been correlated with preservation of native higher order structure and/or molecular mobility in the solid matrix, with varying success. In the studies reported here, we used solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS) to study the conformation of an IgG1 monoclonal antibody (mAb) in lyophilized solids and related the extent of ssHDX to aggregation during storage in the solid phase...
February 5, 2018: Molecular Pharmaceutics
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