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Jones T.D.,Abzena | Carter P.J.,Genentech | Pluckthun A.,University of Zurich | Vasquez M.,Adimab Inc. | And 31 more authors.
mAbs | Year: 2016

A n important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a –mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies. © 2016, Tim D. Jones….

Mistry P.,Glaxosmithkline | Reid J.,Glaxosmithkline | Pouliquen I.,Glaxosmithkline | McHugh S.,Addenbrookes Center for Clinical Investigation | And 6 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2014

Objective: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK1070806, a novel IgG1 mAb that neutralizes human interleukin (IL)-18. Methods: In this first-time-in-human (FTIH) study, cohorts of healthy and obese subjects were randomly allocated to receive single doses of GSK1070806 (0.008 - 10 mg/kg) or placebo. Blood was sampled ≤ 274 days post-dosing, and safety monitored. Results: GSK1070806 was generally well tolerated. The most common AEs were nasopharyngitis and headache, arising as frequently in the placebo as in the active drug groups; most AEs were mild to moderate and unrelated to dose level. There were no allergic, delayed-type hypersensitivity, or infusion-related reactions and the incidence of immunogenicity was low. GSK1070806 plasma pharmacokinetic profiles were comparable in healthy and obese subjects; there was no major deviation from dose proportionality for AUC and Cmax although a trend for dose-dependent increase in t1/2 was observed. Serum drug-bound IL-18 levels increased post-dosing and were sustained for a long time-period following GSK1070806 administration. Ex-vivo whole blood assay demonstrated prolonged pharmacological activity of GSK1070806 as determined by its primary immunological mechanism of action, inhibition of IL-18-induced IFN-γ production. Conclusion: GSK1070806 warrants clinical investigation in patients. ©2014 Dustri-Verlag Dr. K. Feistle.

Koch A.,Addenbrookes Center for Clinical Investigation | Kitchiner P.,Addenbrookes Center for Clinical Investigation | Dewit O.,Addenbrookes Center for Clinical Investigation | Fina P.,Glaxosmithkline | And 2 more authors.
Otology and Neurotology | Year: 2011

Objective: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety and depression. The novel neurokinin-1 receptor antagonist, vestipitant, has anxiolytic properties and a good safety profile. Vestipitant was investigated for potential effect against chronic tinnitus as a stand-alone treatment and in conjunction with a selective serotonin reuptake inhibitor, paroxetine. Study Design: Randomized, double-blind, crossover study. Setting: Tertiary neurotologic and audiologic center with additional referrals from a secondary university hospital center. Patients: Twenty-four adult patients with tinnitus were randomized into the study. Main Outcome Measures: Visual analogue scale (VAS) measurements of tinnitus loudness (intensity), pitch and distress, VAS measurements of arousal/anxiety, Tinnitus Handicap Inventory, Quick Inventory of Depressive Symptomatology, and plasma concentrations of trial drugs. Results: No statistically significant treatment benefit effect was detected for tinnitus (intensity, pitch, and distress) VAS scores, arousal-anxiety VAS scores, Tinnitus Handicap Inventory, or tinnitus aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of tinnitus intensity and distress scores was observed after vestipitant compared with placebo for the mean data collected over the treatment period. No relevant differences in vestipitant plasma concentrations were observed between the subjects given the combination with paroxetine and those receiving vestipitant alone. No specific relationships were observed between tinnitus intensity and vestipitant plasma concentrations. Conclusion: Although well-tolerated vestipitant, alone or in combination with paroxetine, was not effective in ameliorating tinnitus in this patient group. Copyright © 2011 Otology & Neurotology, Inc.

Bennett M.R.,Addenbrookes Center for Clinical Investigation | Sinha S.,Addenbrookes Center for Clinical Investigation | Owens G.K.,University of Virginia
Circulation Research | Year: 2016

The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis. © 2016 The Authors.

Harzheim D.,Babraham Institute | Harzheim D.,Caesar Research Center | Talasila A.,Babraham Institute | Movassagh M.,Addenbrookes Center for Clinical Investigation | And 5 more authors.
Channels | Year: 2010

Cardiac hypertrophy is associated with profound remodeling of Ca 2+ signaling pathways. During the early, compensated stages of hypertrophy, Ca2+ fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca2+ homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca2+ release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca2+ store are primarily responsible for the Ca2+ flux that induces myocyte contraction, a role for Ca2+ release via the inositol 1,4,5-trisphosphate receptor (InsP3R) in cardiac physiology has also emerged. Specifically, InsP3-induced Ca2+ signals generated following myocyte stimulation with an InsP3-generating agonist (e.g., endothelin, ET-1), lead to modulation of Ca2+ signals associated with excitation-contraction coupling (ECC) and the induction of spontaneous Ca2+ release events that cause cellular arrhythmia. Using myocytes from spontaneously hypertensive rats (SHR), we recently reported that expression of the type 2 InsP3R (InsP3R2) is significantly increased during hypertrophy. Notably, this increased expression was restricted to the junctional SR in close proximity to RyRs. There, enhanced Ca 2+ release via InsP3Rs serves to sensitize neighboring RyRs causing an augmentation of Ca2+ fluxes during ECC as well as an increase in non-triggered Ca2+ release events. Although the sensitization of RyRs may be a beneficial consequence of elevated InsP 3R expression during hypertrophy, the spontaneous Ca2+ release events are potentially of pathological significance giving rise to cardiac arrhythmia. InsP3R2 expression was also increased in hypertrophic hearts from patients with ischemic dilated cardiomyopathy and aortically-banded mice demonstrating that increased InsP3R expression may be a general phenomenon that underlies Ca2+ changes during hypertrophy. © 2010 Landes Bioscience.

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