Porter J.,UCB Celltech
Expert Opinion on Therapeutic Patents | Year: 2010
Importance of the field: c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials. Areas covered by this review: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy. What the reader will gain: Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic. Take home message: This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents. © 2010 Informa UK Ltd.
Gorter J.A.,University of Amsterdam |
Iyer A.,University of the Netherlands |
White I.,UCB Celltech |
Colzi A.,UCB Pharma |
And 4 more authors.
Neurobiology of Disease | Year: 2014
Since aberrant miRNA expression has been implicated in numerous brain diseases, we studied miRNA expression and miRNA regulation of important signaling pathways during temporal lobe epileptogenesis in order to identify possible targets for epilepsy therapy.The temporal profile of miRNA expression was analyzed in three brain regions (CA1; dentate gyrus, DG; parahippocampal cortex, PHC) associated with epileptogenesis in a rat model for temporal lobe epilepsy. Tissue was obtained after electrically-induced status epilepticus (SE) at 1. day (n=5), 1. week (n=5) and 3-4. months (n=5), and compared with control tissue (n=10) using the Exiqon microRNA arrays which contain capture probes targeting all miRNAs for rat (p<. 0.01, and a 1.5 fold up- or downregulation). Expression of three blood plasma miRNAs from the same group of rats was also investigated in rats in order to determine whether plasma miRNAs could serve as potential biomarkers of the epileptogenic process. Molecular pathways potentially altered by the expression of multiple miRNAs were identified using a web-based algorithm, DIANA.In CA1 and DG, more upregulated than downregulated miRNAs were present during each stage after SE. The highest numbers of upregulated miRNAs were encountered during the chronic stage in the DG. In PHC, a high number of downregulated miRNAs were detected. Key pathways involved, based upon quantitatively altered miRNA expression were: axon guidance, MAPK signaling pathway, focal adhesion, TGFβ, ErbB-, Wnt- and mTOR signaling, and regulation of actin skeleton. Expression of plasma miRNAs was differentially regulated after induction of SE.This study identified several signaling pathways possibly involved in temporal lobe epileptogenesis, not previously indicated by RNA microarray studies. These include miRNAs that regulate the ErbB and Wnt pathways and focal adhesion, which may represent interesting new targets for therapeutic interventions. © 2013 Elsevier Inc.
Makwana R.,King's College London |
Gozzard N.,UCB Celltech |
Spina D.,King's College London |
Page C.,King's College London
British Journal of Pharmacology | Year: 2012
Background and purpose: TNF-α is an inflammatory cytokine implicated in the pathogenesis of asthma and it causes airway inflammation, bronchoconstriction and airway hyperresponsiveness to a number of spasmogens following inhalation. Experimental approach: We compared contractions of guinea pig isolated trachea incubated with saline or TNF-α for 1, 2 or 4 days to electrical field stimulation (EFS), 5-HT or methacholine. In addition, we compared bronchoconstriction in anaesthetized guinea pigs 6 h after intratracheal instillation of saline or TNF-α to vagal nerve stimulation, i.v. 5-HT or methacholine. Differential counts were performed on the bronchoalvelolar lavage fluid (BALF). Key results: Maximum contractions to methacholine, 5-HT and EFS were not different between freshly prepared and saline-incubated tissues. Exposure to TNF-α concentration-dependently potentiated contractions to 5-HT and EFS, but not methacholine. All contractions were atropine-sensitive, but not hexamethonium-sensitive. 5-HT-evoked contractions were inhibited by ketanserin or epithelial denudation. Only EFS-evoked contractions were tetrodotoxin-sensitive. Vagal stimulation, i.v. 5-HT or MCh caused a significant atropine-sensitive, frequency- and dose-dependent bronchoconstriction and decreased blood pressure similarly in both saline and TNF-α pre-treated animals. TNF-α potentiated the bronchoconstriction to vagal stimulation and 5-HT, but not MCh. The BALF from saline-treated animals contained predominantly macrophages, whereas that from TNF-α-treated animals contained neutrophils. Conclusions and implications: TNF-α caused airway hyperresponsiveness to nerve stimulation in vivo and increased contractility in vitro. However, responsiveness to MCh was unchanged, suggesting a pre-synaptic action of TNF-α on parasympathetic nerves. TNF-α-induced airway hyperresponsiveness to 5-HT suggested an increased 5-HT 2A receptor-mediated acetylcholine release from epithelial cells. © 2011 The British Pharmacological Society.
Catley M.C.,UCB Celltech
IDrugs | Year: 2010
The International Quality & Productivity Center's (IQPC) Second Asthma & COPD conference, held in Philadelphia, included topics covering new therapeutic developments in the field of asthma and COPD. This conference report highlights selected presentations on mAb treatments for asthma, including targeting IL-5, IL-13, IL-9 and TNFa, CCR3 inhibitors, histamine H4 receptor inhibition, novel mouse models of COPD and inhaled antisense asthma therapies. Investigational drugs discussed include mepolizumab (GlaxoSmithKline plc), benralizumab (BioWa Inc/Kyowa Hakko Kirin Co Ltd/MedImmune LLC), AMG-317 (Amgen Inc/Takeda Bio Development Center Ltd), TPI-ASM-8 (Pharmaxis Ltd) and AIR-645 (Altair Therapeutics Inc). © Thomson Reuters (Scientific) Ltd.
Pacholarz K.J.,University of Edinburgh |
Garlish R.A.,UCB Celltech |
Taylor R.J.,UCB Celltech |
Barran P.E.,University of Edinburgh
Chemical Society Reviews | Year: 2012
The initial stages of drug discovery are increasingly reliant on development and improvement of analytical methods to investigate protein-protein and protein-ligand interactions. For over 20 years, mass spectrometry (MS) has been recognized as providing a fast, sensitive and high-throughput methodology for analysis of weak non-covalent complexes. Careful control of electrospray ionization conditions has enabled investigation of the structure, stability and interactions of proteins and peptides in a solvent free environment. This critical review covers the use of mass spectrometry for kinetic, dynamic and structural studies of proteins and protein complexes. We discuss how conjunction of mass spectrometry with related techniques and methodologies such as ion mobility, hydrogen-deuterium exchange (HDX), protein footprinting or chemical cross-linking can provide us with structural information useful for drug development. Along with other biophysical techniques, such as NMR or X-ray crystallography, mass spectrometry provides a powerful toolbox for investigation of biological problems of medical relevance (204 references). © 2012 The Royal Society of Chemistry.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Collaborative Research & Development | Award Amount: 720.54K | Year: 2015
The current platform antibody purification process deployed in the bioprocesing industry becomes less efficient and less cost-effective to match with high titre upstream technologies. Based on previous feasibility studies using model antibodies, the key aim and objective of this project is to investigate negative chromatography based technologies using real industrial feedstocks to dramatically improve the overall process efficiency issue as described above. The market size in the downstream biopharmaceutical processing sector is ca $3 - 5 billions and it is a global market to play. The successful outcomes of this project will bring enormous potential cost benefits to the industry.
Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 5.84M | Year: 2011
In the 1980s it began to be possible to produce potentially unlimited quantities of human proteins by placing the gene defining them in a simple organism such as yeast. From this grew a new kind of medicine capable of treating conditions such as severe arthritis, haemophilia, growth deficiency, and some cancers that previously had no satisfactory treatments. As well as having great clinical value the resulting technology has become the basis of a new and fastest growing part of the pharmaceutical industry, described as biopharmaceuticals. Because the molecules involved are proteins, they are orders of magnitude larger and more complex than conventional drugs such as aspirin and their processing is much more demanding. They are also so complex that they cannot in general be characterised with precision except in relation to the methods by which they are made. That means the capacity to precisely define such processes is critical to clinical safety and commercial success. Full scale trials of the processes are so costly they can only be conducted once clinical promise is established but, given the number of factors governing processing of even first generation products, there have often been hold-ups so extensive as to delay availability to patients. UCL has pioneered micro scale methods that are sufficiently good at predicting efficient conditions for large scale performance that far fewer and better focussed large scale trials suffice. That resolves part of the problem but an even greater challenge is now emerging. The early biopharmaceuticals were in general the easiest ones to produce. The final scales were also relatively modest. Now, the next generation of biopharmaceuticals are more complex materials and with rising demand the scales are far larger so that processes push the boundaries of the possible. The combined complexity of the product and the process with so many variables to consider means that the managers need better systematic means of supporting their decisions. Already the cost of developing a single biopharmaceutical can exceed 0.7 billion and take 10 years. With more advanced biopharmaceuticals these figures tend to rise and yet the worlds governments are facing a healthcare cost crisis with more older people. They therefore exert pressure on companies to reduce prices. Because the public wishes to have medicines that do not pose risks, regulations become ever more stringent so they are a major factor in defining the bioprocess. This also adds to the need for managers to have sector-specific decisional-support aids well grounded in the detailed engineering of the processes. Finally, it is now possible to apply molecular engineering to proteins and vaccines to enhance their therapeutic properties but this can also cause serious bioprocessing problems. The research vision developed with detailed input from UK industry experts will apply these methods as the foundation for another step change whereby much faster and lower cost information can be gathered and integrated with advanced decisional techniques to give managers a better foundation on which to base their policies. The academic team from leading UK universities provides the necessary continuum of skills needed to assess the ease of manufacture of novel drugs, the costs of processing and of delivery to patients. We will work with companies to test the outcomes to ensure they are well proven prior to use on new biopharmaceuticals. This will cut costs so that all the patients who might benefit can receive them and at the earliest possible date achieved within the severely restricted budgets now available to the NHS.
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.69M | Year: 2015
The market for recombinant proteins, including biopharmaceuticals, industrial enzymes and membrane proteins, is estimated to be about 78 billion Euro and rising. A high proportion of the target proteins are produced in bacteria, where secretion out of the cytoplasm is a favoured strategy. However, current production platforms have severe limitations and cannot handle many secreted enzymes and membrane proteins. There is an overwhelming need for new production systems that can deliver these products in greater yields, with higher quality and at lower costs. The ProteinFactory ETN will meet these challenges through the provision of a suite of super-secreting strains with unique capabilities. These strains will be engineered to bypass major production bottlenecks such as secretion stress, and will be capable of secreting an unprecedented range of target molecules. Equally important will be the training of a new generation of researchers, versed in Systems and Synthetic Biology approaches. The ProteinFactory project will involve extensive collaboration between 6 academic Institutes, who provide world-leading expertise in synthetic biology and protein secretion, and 5 non-academic partners who include some of the worlds premier biotechnology companies. Training will be inter-sectoral from the outset, with every ESR undertaking extensive secondments within the non-academic partners in order to encourage an entrepreneurial mind-set. The project is furthermore explicitly multi-disciplinary in scope, with two of the five research work packages dominated by theoretical approaches. Based on a responsible innovation approach and with a clear focus on inter-sectoral collaboration, ProteinFactory will deliver a cohort of superbly-trained scientists, put the industrial and SME partners at the forefront of global competition and reinforce European innovation potentials with growth and job creation.
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-IAPP-2008 | Award Amount: 1.09M | Year: 2009
The Foldappi proposal aims to investigate the potential of aromatic amide Foldamers to disrupt protein-protein interactions. The scientific goals of the project include: 1. development of synthetic methods to build foldamers with different R-group chemistries 2. development of strategies to target foldamers to protein surfaces 3. measuring in vitro properties of foldamer(s) to assess ADME profiles of these molecules In this proposal we propose to explore the use of quinoline-derived aromatic amide foldamers developed at the University of Bordeaux to inhibit protein-protein interactions, namely the interaction between interleukin 4 (IL-4) and its receptor. These foldamers have a very well defined structure that lends itself to the rational design of substituents and the production of focused combinatorial libraries of foldamers capable of interacting with the IL4/IL-4R binding epitope. They are also large enough to block a protein-protein interaction, a feat that is not possible with small molecules. The cytokine IL-4 is a key regulator of the immune system determining the formation of immune cells and immunoglobulin class switching. IL-4 is critically involved in misguided immune reactions during atopic diseases as allergy and asthma. In spite of its importance as a drug target, no small molecule inhibitor of the Il-4/IL-4R has been reported so far, warranting the use of foldamers to do the same. The three partners involved in this cooperation, namely UCB Pharma, Universit Bordeaux I and Universitt Wrzburg each have unique expertises necessary to bring this project to completion. This combination will produce breakthrough knowledge and insights into developing chemistries that can impact in health and medical fields. Moreover, this project will contribute to the personal development of the scientists involved by improving their interdisciplinary knowledge, as well as their communication and experimental skills.
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 91.93K | Year: 2011
Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.