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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.


Olsson T.S.G.,University College London | Olsson T.S.G.,Cambridge Crystallographic Data Center | Ladbury J.E.,University College London | Ladbury J.E.,University of Texas M. D. Anderson Cancer Center | And 3 more authors.
Protein Science | Year: 2011

The extent of enthalpy-entropy compensation in protein-ligand interactions has long been disputed because negatively correlated enthalpy (ΔH) and entropy (TΔS) changes can arise from constraints imposed by experimental and analytical procedures as well as through a physical compensation mechanism. To distinguish these possibilities, we have created quantitative models of the effects of experimental constraints on isothermal titration calorimetry (ITC) measurements. These constraints are found to obscure any compensation that may be present in common data representations and regression analyses (e.g., in ΔH vs. -TΔS plots). However, transforming the thermodynamic data into ΔΔ-plots of the differences between all pairs of ligands that bind each protein diminishes the influence of experimental constraints and representational bias. Statistical analysis of data from 32 diverse proteins shows a significant and widespread tendency to compensation. ΔΔH versus ΔΔG plots reveal a wide variation in the extent of compensation for different ligand modifications. While strong compensation (ΔΔH and 2TΔΔS opposed and differing by < 20% in magnitude) is observed for 22% of modifications (twice that expected without compensation), 15% of modifications result in reinforcement (ΔΔH and 2TΔΔS of the same sign). Because both enthalpy and entropy changes arise from changes to the distribution of energy states on binding, there is a general theoretical expectation of compensated behavior. However, prior theoretical studies have focussed on explaining a stronger tendency to compensation than actually found here. These results, showing strong but imperfect compensation, will act as a benchmark for future theoretical models of the thermodynamic consequences of ligand modification. Published by Wiley-Blackwell. © 2011 The Protein Society.


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.


Bender B.,Genentech | Bender B.,Uppsala University | Leipold D.D.,Genentech | Xu K.,Genentech | And 3 more authors.
AAPS Journal | Year: 2014

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n=34) and cynomolgus monkeys (n=18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are ≥3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints. © 2014 American Association of Pharmaceutical Scientists.


Grant
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.


Grant
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.


Grant
Agency: Cordis | 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.


Grant
Agency: Cordis | 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.


Marenzana M.,UCB Celltech | Marenzana M.,Imperial College London | Greenslade K.,UCB Celltech | Eddleston A.,UCB Celltech | And 4 more authors.
Arthritis and Rheumatism | Year: 2011

Objective Exposure to supraphysiologic levels of glucocorticoid drugs is known to have detrimental effects on bone formation and linear growth. Patients with sclerosteosis lack the bone regulatory protein sclerostin, have excessive bone formation, and are typically above average in height. This study was undertaken to characterize the effects of a monoclonal antibody to sclerostin (Scl-AbI) in mice exposed to dexamethasone (DEX). Methods Young mice were concomitantly treated with DEX (or vehicle control) and Scl-AbI antibody (or isotype-matched control antibody [Ctrl-Ab]) in 2 independent studies. Linear growth, the volume and strength of the bones, and the levels of bone turnover markers were analyzed. Results In DEX-treated mice, Scl-AbI had no significant effect on linear growth when compared to control treatment (Ctrl-Ab). However, in mice treated with DEX and Scl-ABI, a significant increase in trabecular bone at the femoral metaphysis (bone volume/total volume +117% versus Ctrl-Ab-treated mice) and in the width and volume of the cortical bone at the femoral diaphysis (+24% and +20%, respectively, versus Ctrl-Ab-treated mice) was noted. Scl-AbI treatment also improved mechanical strength (as assessed by 4-point bending studies) at the femoral diaphysis in DEX-treated mice (maximum load +60% and ultimate strength +47% in Scl-AbI-treated mice versus Ctrl-Ab-treated mice). Elevated osteocalcin levels were not detected in DEX-treated mice that received Scl-AbI, although levels of type 5b tartrate-resistant acid phosphatase were significantly lower than those observed in mice receiving DEX and Ctrl-Ab. Conclusion Scl-AbI treatment does not prevent the detrimental effects of DEX on linear growth, but the antibody does increase both cortical and trabecular bone and improves bone mechanical properties in DEX-treated mice. Copyright © 2011 by the American College of Rheumatology.


Grant
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.

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