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Hannah Frizzell, Tiffany Ohlsen, Kim A Woodrow
Biologics are the most rapidly growing class of therapeutics, but commonly suffer from low stability. Peroral administration of these therapeutics is an attractive delivery route; however, this route introduces unique physiological challenges that increase the susceptibility of proteins to lose function. Formulation of proteins into biomaterials, such as electrospun fibers, is one strategy to overcome these barriers, but such platforms need to be optimized to ensure protein stability and maintenance of bioactivity during the formulation process...
September 20, 2017: International Journal of Pharmaceutics
Evdoxia Gourbatsi, Jane F Povey, C Mark Smales
OBJECTIVES: There are a number of blockbuster monoclonal antibodies on the market used for the treatment of a variety of diseases. Although the formulation of many antibodies is achieved in 'platform' formulations, some are so difficult to formulate that it can result in an inability to develop a finished drug product. Further, a large number of antibody-inspired or-based molecules are now being developed and assessed for biotherapeutic purposes and less is understood around the required active protein drug concentrations, excipients and additives required in final product formulations...
September 23, 2017: Biotechnology Letters
Agustina Gugliotta, Natalia Ceaglio, Marina Etcheverrigaray, Ricardo Kratje, Marcos Oggero
Glycoengineering by N- and/or O-hyperglycosylation represents a procedure to introduce potential sites for adding N- and/or O-glycosyl structures to proteins with the aim of producing biotherapeutics with improved pharmacodynamic and pharmacokinetic properties. In this chapter, a detailed description of the steps routinely performed to generate new proteins having high content of N- and/or O-glycosyl moieties is carried out. The rational strategy involves the initial stage of designing N- and/or O-hyperglycosylated muteins to be expressed by mammalian cells and includes the upstream and downstream processing stages necessary to develop hyperglycosylated versions of the proteins of interest with the purpose of beginning the long road toward producing biobetters...
2018: Methods in Molecular Biology
Rebecca G Watson, Adrienne Clements-Egan, Allen Schantz, Mark Ware, Bonnie Wu, Tong-Yuan Yang, Gopi Shankar, Joseph C Marini
Bioanalytical methods must enable the delivery of data that meet sound, scientifically justified, fit-for-purpose criteria. At early phases of biotherapeutic drug development, suitable criteria of a ligand-binding assay could be met for pharmacokinetic (PK) in-study sample testing without a full validation defined by regulatory guidelines. To ensure fit-for-purpose methods support PK testing through all phases of biotherapeutic development, three tiers of method validation - regulatory, scientific and research validations - are proposed...
September 18, 2017: Bioanalysis
Unyong Kim, Myung Jin Oh, Youngsuk Seo, Yinae Jeon, Joon-Ho Eom, Hyun Joo An
AIM: Glycosylation of recombinant human erythropoietins (rhEPOs) is significantly associated with drug's quality and potency. Thus, comprehensive characterization of glycosylation is vital to assess the biotherapeutic quality and establish the equivalency of biosimilar rhEPOs. However, current glycan analysis mainly focuses on the N-glycans due to the absence of analytical tools to liberate O-glycans with high sensitivity. We developed selective and sensitive method to profile native O-glycans on rhEPOs...
September 18, 2017: Bioanalysis
Wei Fu, Bo An, Xue Wang, Jun Qu
No abstract text is available yet for this article.
September 18, 2017: Bioanalysis
Daniel J Denmark, Robert H Hyde, Charlotte Gladney, Manh-Huong Phan, Kirpal S Bisht, Hariharan Srikanth, Pritish Mukherjee, Sarath Witanachchi
Conventional therapeutic techniques treat patients by delivering biotherapeutics to the entire body. With targeted delivery, biotherapeutics are transported to the afflicted tissue reducing exposure to healthy tissue. Targeted delivery devices are minimally composed of a stimuli responsive polymer allowing triggered release and magnetic nanoparticles enabling targeting as well as alternating magnetic field (AMF) heating. Although more traditional methods, like emulsion polymerization, have been used to realize such devices, the synthesis is problematic...
November 2017: Drug Delivery
Ivana Knezevic, Elwyn Griffiths
The most advanced regulatory processes for complex biological products have been put in place in many countries to provide appropriate regulatory oversight of biotherapeutic products in general, and similar biotherapeutics in particular. This process is still ongoing and requires regular updates to national regulatory requirements in line with scientific developments and up-to-date standards. For this purpose, strong knowledge of and expertise in evaluating biotherapeutics in general and similar biotherapeutic products, also called biosimilars, in particular is essential...
September 14, 2017: Annals of the New York Academy of Sciences
Ju-Hyung Shin, Jin-Yong Noh, Kwon-Ho Kim, Jae-Keun Park, Ji-Ho Lee, Seong Dong Jeong, Dae-Yoon Jung, Chang-Seon Song, Yeu-Chun Kim
Microneedles are the micrometer size devices used for the delivery of vaccines and biotherapeutics. In order to increase the vaccine efficacy and reduce the antigen dose, there is a significant need to find some adjuvants for the microneedle vaccination. In this study, zymosan, which is the cell wall preparation of Saccharomyces cerevisiae, or poly (I:C) was coated on a microneedle with inactivated influenza virus, and then immunized into BALB/c mouse to determine the immunogenicity, protection and synergetic effect between two adjuvants...
September 7, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
L Zorzela, S K Ardestani, L V McFarland, S Vohra
Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent and treat various diseases. Recent clinical research has focused on living strains of probiotics, but use in high-risk patients and potential adverse reactions including bacteremia has focused interest on alternatives to the use of live probiotics. We searched MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Alt Health Watch, Web of Science, Scopus, PubMed, from inception to February 14, 2017 for randomised controlled trials involving modified probiotic strains...
September 8, 2017: Beneficial Microbes
Nikhil Kateja, Devashish Kumar, Avinash Godara, Vijesh Kumar, Anurag S Rathore
Achieving consistent product quality of a biotherapeutic is a major target for any biopharmaceutical manufacturer, even more for a biosimilar producer as comparability with the innovator product is a regulatory expectation. The complexity of biotherapeutic products and their tedious manufacturing processes, however, make this a non-trivial exercise. The primary motivation of this work is to develop an integrated chromatographic platform for purification of monoclonal antibody (mAb) therapeutics that can deliver the desired separation of both charge variants and aggregates, in addition to the process related impurities like host cell proteins (HCP) and host cell DNA...
September 7, 2017: Biotechnology Journal
Rohit Bansal, Sameer Dhawan, Soumili Chatterjee, Govind Maurya, V Haridas, Anurag Singh 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 (-80ºC to -20ºC). However, reliable storage at these temperatures can be a challenge, particularly in developing and underdeveloped countries and hence lately there has been a renewed interest in creating formulations that would offer stability at higher temperatures (25ºC to 55ºC)...
September 7, 2017: Bioconjugate Chemistry
H D Roberts-Dalton, A Cocks, J M Falcon-Perez, E J Sayers, J P Webber, P Watson, A Clayton, A T Jones
Extracellular vesicles, including exosomes, are naturally derived nanovesicles generated in and released by numerous cell types. As extracellular entities they have the capacity to interact with neighbouring cells and distant tissues and affect physiological processes as well as being implicated in numerous diseases including tumorigenesis and neurodegeneration. They are also under intense investigation as delivery vectors for biotherapeutics. The ways in which EVs interact with recipient cells to influence cell physiology and deliver a macromolecular payload are at the early stages of exploration...
September 21, 2017: Nanoscale
Sumit K Singh, Deepak Kumar, Anurag S Rathore
Estimating impact of the various product-related variants and impurities on a biotherapeutic's safety and efficacy is an essential requirement in the quality by design paradigm. In view of the limited role that clinical studies offer in this regard, we demonstrate a preclinical approach to achieve this for granulocyte colony-stimulating factor (GCSF). While our repeated-dose toxicity data suggest that these variants do not elicit any adverse effects or histopathological changes, aggregated GCSF impurity caused sluggishness in animal behavior manifested by a possible muscular injury...
September 5, 2017: AAPS Journal
Jens Walter, María X Maldonado-Gómez, Inés Martínez
Strategies aimed at modulating the gut microbiota by using live microbes range from single strains (probiotics or live biotherapeutics) to whole non-defined fecal transplants. Although often clinically efficacious, our understanding on how microbial-based strategies modulate gut microbiome composition and function is vastly incomplete. In this review, we present a framework based on ecological theory that provides mechanistic explanations for the findings obtained in studies that attempted to modulate the gut microbiota of humans and animals using live microbes...
August 31, 2017: Current Opinion in Biotechnology
Sarah Flora Jonas, Cyprien Mbogning, Philippe Broët
Several tests have been recently implemented in the nonparametric comparison of current status survival data. However, they are not suited for the situation of crossing hazards. In this setting, we propose a new test specifically designed for crossing hazards alternatives. The proposed test is compared to classical implemented tests through simulations mimicking crossing hazards situations with various schemes of censoring. The results show that the proposed test has a correct type I error and generally outperforms the existing methods...
August 30, 2017: Statistics in Medicine
Arpad Szoor, Abishek Vaidya, Mireya Paulina Velasquez, Zhuyong Mei, Daniel L Galvan, David Torres, Adrian Gee, Andras Heczey, Stephen Gottschalk
The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)(+) HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL)...
September 15, 2017: Molecular Therapy Oncolytics
Chapman Wright, Christina Alves, Scott Estes, John Pieracci, Rashmi Kshirsagar
The Biogen upstream platform is capable of delivering equivalent quality material throughout the cell line generation process. This allows us to rapidly deliver high quality biopharmaceuticals to patients with unmet medical needs. The drive to reduce time-to-market led the cell engineering group to develop an expression system that can enable this strategy. We have developed a clonal CHO host cell line that can routinely produce consistent antibody material at high titers throughout the cell line generation process...
August 26, 2017: Biotechnology Progress
Youngbin Baek, Deyu Yang, Nripen Singh, Abhiram Arunkumar, Sanchayita Ghose, Zheng Jian Li, Andrew L Zydney
Diafiltration is used for final formulation of essentially all biotherapeutics. Several studies have demonstrated that buffer/excipient concentrations in the final diafiltered product can be different than that in the diafiltration buffer due to interactions between buffer species and the protein product. However, recent work in our lab has shown variations in solution pH that are largely independent of the protein concentration during the first few diavolumes. Our hypothesis is that these pH variations are due to non-idealities in the acid-base equilibrium coefficient...
August 25, 2017: Biotechnology Progress
Gargi Roy, Shu Zhang, Lina Li, Eileen Higham, Herren Wu, Marcello Marelli, Michael A Bowen
Mammalian cell expression systems have become a workhorse for the production of biotherapeutic proteins. As such, there is an ever increasing demand for higher productivity from these expression platforms to reduce manufacturing costs. While great advances have been made in the optimization of culture conditions and cell line selection to improve productivity, protein mis-folding remains a common limitation to high levels of production of therapeutic proteins. Accumulation of mis- and unfolded protein in the endoplasmic reticulum (ER) causes ER stress and initiates the unfolded protein response (UPR) that results in an activation of protein folding machinery, translation attenuation in an effort to proper folding of the newly synthesized peptides or may even lead to apoptosis if the correct folding is not restored...
2017: PloS One
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