Reick C.,Ruhr University Bochum |
Ellrichmann G.,Ruhr University Bochum |
Thone J.,Ruhr University Bochum |
Scannevin R.H.,BiogenIdec Inc. |
And 3 more authors.
Experimental Neurology | Year: 2014
Introduction: Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in C57BL/6 mice by immunization with MOG35-55-peptide. Murine IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action. Results: Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells. Discussion: Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted. © 2014 Elsevier Inc.
Martinez-Paniagua M.A.,University of California at Los Angeles |
Martinez-Paniagua M.A.,Hospital Of Infectologia |
Vega M.I.,University of California at Los Angeles |
Vega M.I.,Hospital Of Oncologia Cmn Siglo Xxi Imss |
And 5 more authors.
Molecular Cancer Therapeutics | Year: 2012
Galiximab (anti-CD80 monoclonal antibody) is a primatized (human IgG1 constant regions and cynomologus macaque variable regions) monoclonal antibody that is currently in clinical trials. Galiximab inhibits tumor cell proliferation through possibly cell signaling-mediated effects. Thus, we hypothesized that galiximab may signal the tumor cells and modify intracellular survival/antiapoptotic pathways such as the NF-κB pathway. This hypothesis was tested using various CD80 + Burkitt B-NHL (non-Hodgkin lymphomas) cell lines as models. Treatment of B-NHL cells with galiximab (25-100 μg/mL) resulted in significant inhibition of NF-κB activity and its target resistant factors such as YY1, Snail, and Bcl-2/Bcl-XL. Treatment of B-NHL cells with galiximab sensitized the tumor cells to both cis- diamminedichloroplatinum(II) (CDDP)- and TRAIL-induced apoptosis. The important roles of YY1- and Snail-induced inhibition by galiximab in the sensitization to CCDP and TRAIL were corroborated following transfection of Raji cells with YY1 or Snail short interfering RNA. The transfected cells were shown to become sensitive to both CCDP-and TRAIL-induced apoptosis in the absence of galiximab. Furthermore, knockdown of YY1 or Snail inhibited Bcl-XL. The involvement of Bcl-XL inhibition in sensitization was corroborated by the use of the pan-Bcl-2 inhibitor 2MAM-3 whereby the treated cells were sensitive to both CDDP- and TRAIL-induced apoptosis. These findings show that galiximab inhibits the NF-κB/Snail/YY1/Bcl-XL circuit that regulates drug resistance in B-NHL and in combination with cytotoxic drugs results in apoptosis. The findings also support the therapeutic application of the combination of galiximab and cytotoxic drugs in the treatment of drug-resistant CD80-positive B-cell malignancies. ©2012 AACR.
Moreno J.A.,Autonomous University of Madrid |
Izquierdo M.C.,Autonomous University of Madrid |
Sanchez-Nino M.D.,Autonomous University of Madrid |
Suarez-Alvarez B.,Hospital Universitario Central Of Asturias |
And 9 more authors.
Journal of the American Society of Nephrology | Year: 2011
Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNFα, and siRNA-mediated knockdown of IκBα all activated NFκB and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NFκB with parthenolide prevented TWEAK- or TNFα-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAKinduced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNFα, downregulate Klotho expression through an NFκB-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD. Copyright © 2011 by the American Society of Nephrology.
White E.S.,University of Michigan |
Brown K.K.,National Jewish Health |
Collard H.R.,University of California at San Francisco |
Conoscenti C.S.,Boehringer Ingelheim Pharmaceuticals |
And 8 more authors.
Annals of the American Thoracic Society | Year: 2014
Although widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well annotated or collected uniformly and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository that will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations that will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF. Copyright © 2014 by the American Thoracic Society
Pollock J.,University College London |
Bolton G.,Pfizer |
Bolton G.,BiogenIdec Inc. |
Coffman J.,Pfizer |
And 3 more authors.
Journal of Chromatography A | Year: 2013
This paper presents an integrated experimental and modelling approach to evaluate the potential of semi-continuous chromatography for the capture of monoclonal antibodies (mAb) in clinical and commercial manufacture. Small-scale single-column experimental breakthrough studies were used to derive design equations for the semi-continuous affinity chromatography system. Verification runs with the semi-continuous 3-column and 4-column periodic counter current (PCC) chromatography system indicated the robustness of the design approach. The product quality profiles and step yields (after wash step optimisation) achieved were comparable to the standard batch process. The experimentally-derived design equations were incorporated into a decisional tool comprising dynamic simulation, process economics and sizing optimisation. The decisional tool was used to evaluate the economic and operational feasibility of whole mAb bioprocesses employing PCC affinity capture chromatography versus standard batch chromatography across a product's lifecycle from clinical to commercial manufacture. The tool predicted that PCC capture chromatography would offer more significant savings in direct costs for early-stage clinical manufacture (proof-of-concept) (~30%) than for late-stage clinical (~10-15%) or commercial (~5%) manufacture. The evaluation also highlighted the potential facility fit issues that could arise with a capture resin (MabSelect) that experiences losses in binding capacity when operated in continuous mode over lengthy commercial campaigns. Consequently, the analysis explored the scenario of adopting the PCC system for clinical manufacture and switching to the standard batch process following product launch. The tool determined the PCC system design required to operate at commercial scale without facility fit issues and with similar costs to the standard batch process whilst pursuing a process change application. A retrofitting analysis established that the direct cost savings obtained by 8 proof-of-concept batches would be sufficient to pay back the investment cost of the pilot-scale semi-continuous chromatography system. © 2013 Elsevier B.V.
Wang R.,University of Arizona |
Rossomando A.,BiogenIdec Inc. |
Sah D.W.Y.,BiogenIdec Inc. |
Ossipov M.H.,University of Arizona |
And 2 more authors.
Pain | Year: 2014
Systemic artemin promotes regeneration of dorsal roots to the spinal cord after crush injury. However, it is unclear whether systemic artemin can also promote peripheral nerve regeneration, and functional recovery after partial lesions distal to the dorsal root ganglion (DRG) remains unknown. In the present investigation, male Sprague Dawley rats received axotomy, ligation, or crush of the L5 spinal nerve or sham surgery. Starting the day of injury, animals received intermittent subcutaneous artemin or vehicle across 2 weeks. Sensory thresholds to tactile or thermal stimuli were monitored for 6 weeks after injury. Immunohistochemical analyses of the DRG and nerve regeneration were performed at the 6-week time point. Artemin transiently reversed tactile and thermal hypersensitivity after axotomy, ligation, or crush injury. Thermal and tactile hypersensitivity reemerged within 1 week of treatment termination. However, artemin-treated rats with nerve crush, but not axotomy or ligation, subsequently showed gradual return of sensory thresholds to preinjury baseline levels by 6 weeks after injury. Artemin normalized labeling for NF200, IB4, and CGRP in nerve fibers distal to the crush injury, suggesting persistent normalization of nerve crush-induced neurochemical changes. Sciatic and intradermal administration of dextran or cholera toxin B distal to the crush injury site resulted in labeling of neuronal profiles in the L5 DRG, suggesting regeneration functional restoration of nonmyelinated and myelinated fibers across the injury site into cutaneous tissue. Artemin also diminished ATF3 and caspase 3 expression in the L5 DRG, suggesting persistent neuroprotective actions. A limited period of artemin treatment elicits disease modification by promoting sensory reinnervation of distal territories and restoring preinjury sensory thresholds. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Baker D.P.,BiogenIdec Inc. |
Pepinsky R.B.,BiogenIdec Inc. |
Brickelmaier M.,BiogenIdec Inc. |
Gronke R.S.,BiogenIdec Inc. |
And 14 more authors.
Journal of Interferon and Cytokine Research | Year: 2010
Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone ®), and an anti-VLA4 monoclonal antibody (Tysabri ®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125â€‰μg administered via the subcutaneous route every 2 or 4 weeks. © 2010, Mary Ann Liebert, Inc.
Ma B.,BiogenIdec Inc. |
Lee W.-C.,BiogenIdec Inc.
Tetrahedron Letters | Year: 2010
The Curtius rearrangement and related reactions are often used to convert carboxylic acids to the corresponding primary amines. However, this reaction often requires harsh conditions for hydrolysis of the isocyanate intermediates to amines, and can also be contaminated by the formation of corresponding ureas due to the reactive nature of the intermediates. We have discovered that by quenching the isocyanate intermediates with sodium trimethylsilanolate, the free amines can be isolated after aqueous workup. This mild and fast procedure provides free amines in one pot with good yields. © 2009 Elsevier Ltd. All rights reserved.
Hu Y.,BiogenIdec Inc. |
Lee X.,BiogenIdec Inc. |
Shao Z.,BiogenIdec Inc. |
Apicco D.,BiogenIdec Inc. |
And 4 more authors.
Cell Death and Disease | Year: 2013
The p75 neurotrophin receptor (p75NTR) is a known mediator of b-amyloid (Ab)-induced neurotoxicity implicated in Alzheimer's disease (AD). Here, we demonstrate that death receptor 6 (DR6) binds to p75NTR and is a component of the p75NTR signaling complex responsible for Ab-induced cortical neuron death. Cortical neurons isolated from either DR6 or p75NTR null mice are resistant to Aβ-induced neurotoxicity. Blocking DR6 function in cortical neurons by anti-DR6 antibodies that block the binding of DR6 to p75NTR receptor complex or by a dominant negative DR6 construct lacking the cytoplasmic signaling death domain attenuates Ab-induced caspase 3 activation and cell death. DR6 expression is upregulated in AD cortex and correlates with elevated neuronal death. Targeting the disruption of the DR6/p75NTR complex to prevent Ab cytotoxicity represents a new approach for the treatment of neurodegenerative disorders such as AD. © 2013 Macmillan Publishers Limited All rights reserved.
PubMed | BiogenIdec Inc. and University of Arizona
Type: Journal Article | Journal: Pain | Year: 2014
Systemic artemin promotes regeneration of dorsal roots to the spinal cord after crush injury. However, it is unclear whether systemic artemin can also promote peripheral nerve regeneration, and functional recovery after partial lesions distal to the dorsal root ganglion (DRG) remains unknown. In the present investigation, male Sprague Dawley rats received axotomy, ligation, or crush of the L5 spinal nerve or sham surgery. Starting the day of injury, animals received intermittent subcutaneous artemin or vehicle across 2weeks. Sensory thresholds to tactile or thermal stimuli were monitored for 6weeks after injury. Immunohistochemical analyses of the DRG and nerve regeneration were performed at the 6-week time point. Artemin transiently reversed tactile and thermal hypersensitivity after axotomy, ligation, or crush injury. Thermal and tactile hypersensitivity reemerged within 1week of treatment termination. However, artemin-treated rats with nerve crush, but not axotomy or ligation, subsequently showed gradual return of sensory thresholds to preinjury baseline levels by 6weeks after injury. Artemin normalized labeling for NF200, IB4, and CGRP in nerve fibers distal to the crush injury, suggesting persistent normalization of nerve crush-induced neurochemical changes. Sciatic and intradermal administration of dextran or cholera toxin B distal to the crush injury site resulted in labeling of neuronal profiles in the L5 DRG, suggesting regeneration functional restoration of nonmyelinated and myelinated fibers across the injury site into cutaneous tissue. Artemin also diminished ATF3 and caspase 3 expression in the L5 DRG, suggesting persistent neuroprotective actions. A limited period of artemin treatment elicits disease modification by promoting sensory reinnervation of distal territories and restoring preinjury sensory thresholds.