Amaravadi L.,BiogenIdec |
Song A.,Genentech |
Myler H.,Bristol Myers Squibb |
Thway T.,Amgen Inc. |
And 45 more authors.
Bioanalysis | Year: 2015
The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5 day, week-long event-A Full Immersion Bioanalytical Week-specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS and LBA approaches, including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 3 discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Part 1 (small molecule bioanalysis using LCMS) and Part 2 (hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in volume 7, issues 22 and 23 of Bioanalysis, respectively. © 2015 Future Science Ltd.
PubMed | Eurofins, UCB Pharma, Sanofi S.A., Bristol Myers Squibb and 19 more.
Type: Journal Article | Journal: Bioanalysis | Year: 2015
The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5 day, week-long event - A Full Immersion Bioanalytical Week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS and LBA approaches, including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 3 discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Part 1 (small molecule bioanalysis using LCMS) and Part 2 (hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in volume 7, issues 22 and 23 of Bioanalysis, respectively.
Vahle J.L.,Lilly Research Laboratories |
Finch G.L.,Pfizer |
Heidel S.M.,Lilly Research Laboratories |
Hovland Jr. D.N.,Amgen |
And 7 more authors.
Toxicologic Pathology | Year: 2010
An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling. Copyright © 2010 by The Author(s).
Qian J.,University of Pennsylvania |
Zheng H.,University of Pennsylvania |
HuangFu W.-C.,University of Pennsylvania |
Liu J.,University of Pennsylvania |
And 4 more authors.
PLoS Pathogens | Year: 2011
An ability to sense pathogens by a number of specialized cell types including the dendritic cells plays a central role in host's defenses. Activation of these cells through the stimulation of the pathogen-recognition receptors induces the production of a number of cytokines including Type I interferons (IFNs) that mediate the diverse mechanisms of innate immunity. Type I IFNs interact with the Type I IFN receptor, composed of IFNAR1 and IFNAR2 chains, to mount the host defense responses. However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells. Here, we report that the activation of p38 kinase in response to pathogen-recognition receptors stimulation results in a series of phosphorylation events within the IFNAR1 chain of the Type I IFN receptor. This phosphorylation promotes IFNAR1 ubiquitination and acceleing and the protection of activated dendritic cells from the cytotoxic effects of autocrine or paracrine Type I IFN. In this paper we discuss a potential role of this mechanism in regulating the processes of innate immunity. © 2011 Qian et al.
Bossen C.,University of Lausanne |
Bossen C.,University of California at San Diego |
Tardivel A.,University of Lausanne |
Willen L.,University of Lausanne |
And 8 more authors.
European Journal of Immunology | Year: 2011
B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (∼5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Cudkowicz M.E.,Massachusetts General Hospital |
Katz J.,California Pacific Medical Center |
Moore D.H.,California Pacific Medical Center |
O'Neill G.,BiogenIdec |
And 16 more authors.
Amyotrophic Lateral Sclerosis | Year: 2010
More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS. © 2010 Informa UK Ltd.
Zang L.,BiogenIdec |
Frenkel R.,BiogenIdec |
Simeone J.,BiogenIdec |
Lanan M.,BiogenIdec |
And 2 more authors.
Analytical Chemistry | Year: 2011
As more protein biopharmaceuticals are produced using mammalian cell culture techniques, it becomes increasingly important for the biopharmaceutical industry to have tools to characterize the cell culture media and evaluate its impact on the cell culture performance. Exposure of the cell culture media to light, temperature stress, or adventitious introduction of low-level organisms during preparation can lead to the generation of chemical degradants or metabolites of the media components, which are potentially detrimental to the cell culture process. In this work, we applied a liquid chromatography-mass spectrometry based metabolomics methodology for the investigation of a media lot used for a mammalian cell culture process that had resulted in low growth rate and failure to meet required viable cell density (VCD). The study led to the observation of increased levels of tryptophan oxidation products and a riboflavin degradant, lumichrome, in the malfunctioning media lot, relative to working media lots. A compound found 7-fold higher in the working media lots appeared to be tetrahydropentoxyline, a condensation product of glucose and tryptophan. A second compound found at an over 50-fold higher level in the malfunctioning media lot with a proposed molecular formula of C 21H17N3O3 from high-resolution mass spectrometry (HRMS) analysis remains unknown, although it is confirmed to be a degradant of tryptophan in the media. A study of the cell culture media performed under stress conditions using fluorescent light and heat showed that the media powder was highly resistant to light-induced degradation, while solution media could be easily degraded after brief light exposure. It is therefore suspected that inadvertent exposure of the media to light during preparation and storage has resulted in the poor performance of the media causing the low growth and VCD in the cell culture process. © 2011 American Chemical Society.
Linker R.A.,Ruhr University Bochum |
Linker R.A.,Friedrich - Alexander - University, Erlangen - Nuremberg |
Lee D.-H.,Ruhr University Bochum |
Ryan S.,BiogenIdec |
And 15 more authors.
Brain | Year: 2011
Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies. © The Author (2011).