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Slough, United Kingdom

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. Source


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. Source


Kinnear G.,University of Oxford | Wood K.J.,University of Oxford | Marshall D.,UCB Celltech | Jones N.D.,University of Oxford
Transplantation | Year: 2010

Background. OX40 is a member of the tumor necrosis factor receptor superfamily and is a potent T-cell costimulatory molecule. Although the impact of blockade of the OX40-OX40L pathway has been documented in models of autoimmune disease, the effect on allograft rejection is less well defined. Methods. The expression of OX40 and impact of OX40 blockade on BM3 T cells (H2K-reactive, T-cell receptor-transgenic) after stimulation with alloantigen were assessed in vitro by the incorporation of H-thymidine and flow cytometry. In vivo, naïve BM3 or polyclonal CD8+ T cells were transferred into syngeneic recombinase-activating gene mice, which received an H2 skin allograft with and without anti-OX40. Skin allograft survival was monitored, and the proliferation, number, and phenotype of BM3 T cells were determined using flow cytometry. Results. In vitro allogeneic stimulation of CD8+ T cells resulted in OX40 expression, the blockade of which was found to partially inhibit3 H-thymidine incorporation as a result of increased cell death among activated T cells. Similarly, in vivo, anti-OX40 prevented skin allograft rejection mediated by CD8+ T cells. However, after cessation of anti-OX40 therapy, skin allografts were eventually rejected indicating that tolerance had not been induced. Correlating with the in vitro data, analysis of lymph nodes draining skin allografts revealed that OX40 blockade had no effect on the activation and proliferation of BM3 T cells but rather resulted in diminished effector T-cell accumulation. Conclusion. Taken together, these data demonstrate that anti-OX40 attenuates CD8+ T-cell responses to alloantigen by reducing the pool of effector T cells, suggesting that this may be a worthwhile adjunct to preexisting costimulatory molecule-blocking regimens. © 2010 by Lippincott Williams & Wilkins. Source


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.


Chessa T.A.M.,Babraham Institute | Anderson K.E.,Babraham Institute | Hu Y.,Kings College London | Xu Q.,Kings College London | And 3 more authors.
Blood | Year: 2010

The neutrophil nicotinamide adenine dinucleotide phosphate-oxidase is a multisubunit enzyme (comprising gp91phox, p22phox, p67phox, p40phox, p47phox, and Rac) that plays a vital role in microbial killing. The recent discovery of a chronic granulomatous disease patient who expresses a mutant p40phox subunit, together with the development of mouse models of p40phox function, indicate phosphatidylinositol 3-phosphate binding to the PX domain of p40 phox is an important signal for oxidase activation. However, the presence of other conserved residues and domains in p40phox suggest further regulatory roles for this protein. To test this, we introduced wild-type and mutated versions of p40phox into fully differentiated mouse neutrophils by retroviral transduction of p40phox-/- bone marrow progenitors and repopulation of the bone marrow compartment in radiation chimaeras. Phosphorylation of p40phox on threonine 154, but not serine 315, was required for full oxidase activation in response to formylated bacterial peptide fMLP, serumopsonized S aureus, and immunoglobulinopsonized sheep red blood cells. A functional SH3 domain was not required for oxidase activation, and deletion of the entire domain resulted in enhanced oxidase responses. Phosphorylation of threonine 154 in response to S aureus was mediated by protein kinase Cδ and was required for full translocation of p47 phox to phagosomes. These results define an important new element in the physiological activation of the oxidase. © 2010 by The American Society of Hematology. Source

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