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The chemokine CXCL13 has a key role in secondary lymphoid tissue orchestration and lymphoid neogenesis. Transgenic mice deficient in CXCL13 or its receptor CXCR5 have severely impaired lymph node development, lack peritoneal B-lymphocytes and are deficient in circulating antibodies to common bacterial antigens. However, total circulating numbers of B-lymphocytes are slightly elevated and humoral responses to T-dependent or blood-borne antigens are relatively normal. Lymphoid neogenesis is an aberrant process that occurs in chronically inflamed tissue and provides a microenvironment supportive of pathogenic B-cell survival and activation. Here, we describe the impact of therapeutic dosing of a CXCL13 antibody in a mouse model of arthritis, and detail the contribution CXCL13 makes to lymphoid follicle microenvironment, without affecting humoral immune responses., (© 2013 MedImmune Ltd. European Journal of Clinical Investigation © 2013 Stichting European Society for Clinical Investigation Journal Foundation.)

Background and Purpose: For antibody therapies against receptor targets, in vivo outcomes can be difficult to predict because of target-mediated clearance or antigen 'sink' effects. The purpose of this work was to engineer an antibody to the GM-CSF receptor α (GM-CSFRα) with pharmacological properties optimized for chronic, s.c. treatment of rheumatoid arthritis (RA) patients., Experimental Approach: We used an in silico model of receptor occupancy to guide the target affinity and a combinatorial phage display approach for affinity maturation. Mechanism of action and internalization assays were performed on the optimized antibody in vitro before refining the modelling predictions of the eventual dosing in man. Finally, in vivo pharmacology studies in cynomolgus monkeys were carried out to inform the predictions and support future clinical development., Key Results: Antibody potency was improved 8600-fold, and the target affinity was reached. The refined model predicted pharmacodynamic effects at doses as low as 1 mg kg(-1) and a study in cynomolgus monkeys confirmed in vivo efficacy at 1 mg kg(-1) dosing., Conclusions and Implications: This rational approach to antibody drug discovery enabled the isolation of a potent molecule compatible with chronic, s.c. self-administration by RA patients. We believe this general approach enables the development of optimal biopharmaceuticals., (© 2012 MedImmune. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Rheumatoid arthritis is one of the commonest autoimmune diseases affecting 0.8% of the population. Over the last decade the treatment of this chronic disease has been revolutionized by the use of monoclonal antibodies and fusion proteins, targeting molecules like tumour necrosis factor alpha. Nevertheless, approximately one-third of subjects fail to respond to these therapies and therefore significant unmet medical need remains. Following a decade of use, clinical, government and regulatory agency expectations have changed for new antibodies therapies entering this highly competitive area. In this review, we discuss the current advances being made in antibody engineering and how they are being considered and used in the development of the next generation of antibodies to meet future expectations of healthcare providers, physicians and patients. Moreover, we discuss how pattern recognition receptors may provide new antibody tractable targets that may break the cycle of autoimmunity in rheumatoid arthritis., (© 2011 MedImmune Ltd. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background and Purpose: Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15., Experimental Approach: DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor α (IL-15Rα) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic T lymphocyte line-2, M-07e, KIT225). A pharmacodynamic model injecting male C57/BL6 mice with IL-15 or IL-15/IL-15Rα, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized., Key Results: DISC0280 inhibited the binding of IL-15 to IL-15Rα and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15Rα, shared interleukin 2/ interleukin 15 receptor β chain (IL-15Rβ) and common gamma chain (γ(c) ). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15Rβ/γ(c) subunits. Human IL-15 injected into mice caused an increase in NK1.1(+) and CD3(+) cells in the spleen and peripheral blood and these effects were unexpectedly potentiated by giving DISC0280 with human IL-15. This increase in cells caused by DISC0280/IL-15 co-administration was greater than that observed when IL-15 was administered complexed with soluble IL-15Rα., Conclusions and Implications: The ability of DISC0280 to bind to the IL-15Rα-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15Rα. DISC0280 may be therefore suitable as a clinical substitute for IL-15., (© 2010 MedImmune Ltd. British Journal of Pharmacology © 2010 The British Pharmacological Society.)