Burmester G.R.,Humboldt University of Berlin |
Weinblatt M.E.,Brigham and Women's Hospital |
McInnes I.B.,Glasgow Biomedical Research Center |
Porter D.,Gartnavel General Hospital |
And 13 more authors.
Annals of the Rheumatic Diseases | Year: 2013
Objectives: Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocytemacrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA). Methods: Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12. Results: 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% ( p=0.011), 53.8% ( p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP<2.6 (23.1% vs 6.7%, p=0.016), all categories of the American College of Rheumatology (ACR) criteria (ACR20: 69.2% vs 40.0%, p=0.005; ACR50: 30.8% vs 12.0%, p=0.021; ACR70: 17.9% vs 4.0%, p=0.030), and the Health Assessment Questionnaire Disability Index (-0.48 vs -0.25, p=0.005). A biomarker-based disease activity score showed a dose-dependent decrease at week 12, indicating suppression of disease-related biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. Conclusions: Mavrilimumab induced rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA.
Leick M.,Albert Ludwigs University of Freiburg |
Catusse J.,Albert Ludwigs University of Freiburg |
Follo M.,Albert Ludwigs University of Freiburg |
Nibbs R.J.,Glasgow Biomedical Research Center |
And 3 more authors.
Immunology | Year: 2010
The human chemokine receptor CRAM (chemokine receptor on activated macrophages), encoded by the gene CCRL2, is a new candidate for the atypical chemokine receptor family that includes the receptors DARC, D6 and chemocentryx chemokine receptor (CCX-CKR). CRAM is maturation-stage-dependently expressed on human B lymphocytes and its surface expression is up-regulated upon short-term CCL5 exposure. Here, we demonstrate that the homeostatic chemokine CCL19 is a specific ligand for CRAM. In radioactive labelling studies CCL19 bound to CRAM-expressing cells with an affinity similar to the described binding of its other receptor CCR7. In contrast to the known CCL19/CCR7 ligand/receptor pair, CRAM stimulation by CCL19 did not result in typical chemokine-receptor-dependent cellular activation like calcium mobilization or migration. Instead, we demonstrate that CRAM is constitutively recycling via clathrin-coated pits and able to internalize CCL19 as well as anti-CRAM antibodies. As this absence of classical chemokine receptor responses and the recycling and internalization features are characteristic for non-classical chemokine receptors, we suggest that CRAM is the newest member of this group. As CCL19 is known to be critically involved in lymphocyte and dendritic cell trafficking, CCL19-binding competition by CRAM might be involved in modulating these processes. © 2009 The Authors.
Henriques C.M.,University of Lisbon |
Rino J.,University of Lisbon |
Nibbs R.J.,Glasgow Biomedical Research Center |
Graham G.J.,Glasgow Biomedical Research Center |
Barata J.T.,University of Lisbon
Blood | Year: 2010
Interleukin-7 (IL-7) is an essential cytokine for T-cell development and homeostasis. It is well established that IL-7 promotes the transcriptional down-regulation of IL7RA, leading to decreased IL-7Rα surface expression. However, it is currently unknown whether IL-7 regulates the intracellular trafficking and early turn-over of its receptor on ligand binding. Here, we show that, in steady-state T cells, IL-7Rα is slowly internalized and degraded while a significant fraction recycles back to the surface. On IL-7 stimulation, there is rapid IL-7Rα endocytosis via clathrin-coated pits, decreased receptor recycling, and accelerated lysosome and proteasome-dependent degradation. In accordance, the half-life of IL-7Rα decreases from 24 hours to approximately 3 hours after IL-7 treatment. Interestingly, we further demonstrate that clathrin-dependent endocytosis is necessary for efficient IL-7 signal transduction. In turn, pretreatment of T cells with JAK3 or pan-JAK inhibitors suggests that IL-7Rα degradation depends on the activation of the IL-7 signaling effector JAK3. Overall, our findings indicate that IL-7 triggers rapid IL-7Rα endocytosis, which is required for IL-7-mediated signaling and subsequent receptor degradation. © 2010 by The American Society of Hematology.
Gabrielsen M.,Glasgow Biomedical Research Center |
Abdul-Rahman P.S.,University of Malaya |
Isaacs N.W.,University of Glasgow |
Hashim O.H.,University of Malaya |
Cogdell R.J.,Glasgow Biomedical Research Center
Acta Crystallographica Section F: Structural Biology and Crystallization Communications | Year: 2010
Mannose-binding lectin from champedak (Artocarpus integer) is a homotetra-mer with a single-monomer molecular weight of 16 800 Da. Previous work has shown it to bind IgE and IgM, as well as being a mitogen of T cells in humans. Champedak mannose-binding lectin has successfully been used to detect altered glycosylation states of serum proteins. The protein was crystallized at 293 K in space group P212121 (unit-cell parameters a = 76.89, b = 86.22, c = 95.37 Å) and the crystals diffracted to 2.0 Å resolution. © 2010 International Union of Crystallography All rights reserved.
Douce G.,Glasgow Biomedical Research Center |
Ross K.,Glasgow Biomedical Research Center |
Cowan G.,Glasgow Biomedical Research Center |
Ma J.,Glasgow Biomedical Research Center |
Mitchell T.J.,Glasgow Biomedical Research Center
Vaccine | Year: 2010
Induction of immunity at mucosal surfaces is thought to be an essential feature in the protection of the host against the many pathogens that gain access through these surfaces. Here we describe how strong local and systemic immune responses can be generated when proteins are genetically conjugated to pneumolysin (PLY) from Streptococcus pneumoniae. Using green fluorescent protein (eGFP) and PsaA from S. pneumoniae, we have shown that genetic fusion (eGFPPLY and PsaAPLY) is essential to ensure high levels of antigen specific IgG and IgA in the serum and at mucosal surfaces. This form of vaccination is highly effective with antigen specific antibodies detected after a single dose of nanogram quantities of the conjugated proteins. In addition, generation of a non-toxic variant (eGFPΔ6PLY) indicated that while the toxic activity of PLY was not essential for adjuvanticity, it contributed to the magnitude of the response generated. Whilst vaccination with the PsaAPLY fusion proteins did not protect the animals from challenge, these studies confirm the utility of pneumolysin to act as a novel mucosal adjuvant to substantially increase the local and systemic humoral response to genetically fused protein antigens. © 2010 Elsevier Ltd. All rights reserved.