Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

BackgroundAlveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma.MethodsWe utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation.ResultsIL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure.ConclusionsIn summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.

The costimulatory receptor OX40 is expressed on activated T cells and regulates T-cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice. This was accompanied by a decrease in activated and memory CD4 + T cells in the lungs and further analysis revealed that both the Th2 and Th17 populations were inhibited. Improved lung function and decreased HDM-specific antibody responses were also noted. Significantly, efficacy was observed even when anti-OX40 treatment was delayed until after inflammation was established. OX40 blockade also inhibited the release of the Th2 cytokines IL-5 and IL-13 from cells isolated from HDM allergic human donors. Altogether, our data provide evidence of a role of the OX40/OX40L pathway in ongoing allergic lung inflammation and support clinical studies of a blocking OX40 antibody in Th2 high severe asthma patients.Keywords: Allergic asthma r House dust mite r Lung inflammation r Memory T cells r OX40Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction OX40 (also known as CD134, TNFRSF4, ACT35, or TXGP1L) is a membrane-bound receptor belonging to the TNF receptor superfamily, which includes 4-1BB, CD27, CD30, and CD40. This costimulatory receptor is not expressed on resting T cells, but is transiently expressed on activated T cells after ligation of the TCR, with sequential engagement of CD28 and OX40 being required for optimal T-cell proliferation and survival [1]. Ligation of OX40 on activated T cells leads to enhanced cytokine production and proliferation of both CD4 + and CD8 + T cells [2,3] and can contribute to both ongoing Th1 and Th2 responses [4,5]. OX40 costimulationCorrespondence: Diane Marshall e-mail: diane.marshall@ucb.com prolongs T-cell survival beyond the initial effector phase of the immune response and increases the number of memory T cells through inhibition of effector T-cell death. This long-term survival of T cells via OX40 is thought to be a consequence of maintaining high levels of antiapoptotic proteins, such as Bcl-2, 7]. The ligand for OX40, OX40L, is a member of the TNF family and is expressed on activated APC, including B cells, macrophages, Langerhans cells, and dendritic cells (DCs). Other cell types that are reported to express OX40L include mast cells, NK cells, airway smooth muscle cells, endothelial cells, and platelets [8]. * These authors are co-first authors.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1116-1128 Immunomodulation 1117Asthma is a chronic inflammatory disease of the airways in which many cells and mediators are involved. It is now clear that asthma is a heterogenic disease a...

Rozanolixizumab is a fully humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model characterizing the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first-in-human (FIH) rozanolixizumab clinical trial study design, and, ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (i.v.) dose groups, although the PKs were underpredicted for the 1 mg/kg i.v. dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterize the PK FcRn-IgG nonlinear system in response to rozanolixizumab in the FIH data. StudyHighlights WHAT ISTHECURRENTKNOWLEDGEONTHETOPIC?To date, there have been no established semimechanistic models that could be used to translate pharmacokinetic/pharmacodynamic (PK/PD) responses to an anti-human neonatal Fc receptor monoclonal antibody-based therapeutic from preclinical data to humans. WHAT QUESTIONDIDTHISSTUDYADDRESS? Can we create a useful PK/PD model to predict responses to single i.v. doses of rozanolixizumab in humans, based on in vitro data, in vivo data, and knowledge from literature? WHAT DOESTHISSTUDYADDTOOURKNOWLEDGE? This PK/PD model accurately predicted responses to rozanolixizumab in humans, especially at 4 and 7 mg/kg doses from preclinical species. Adjusting model

Changes in pulmonary permeability provide a partial measure of the clinical impact of biocompatible oxygenator use during cardiopulmonary bypass surgery. Previous research has shown that the clearance rate of 99mTc-labelled diethylene triamine penta-acetic acid (99mTc-DTPA) aerosol from the lungs is increased following cardiopulmonary bypass, resulting from an increase in pulmonary permeability. The aerosol clearance rate has been shown to return to normal after a period of 7 days. A blind trial was set up to assess the clinical impact of a biocompatible, Trillium-coated oxygenator compared with a standard oxygenator. In a group of 25 patients 99mTc-DTPA aerosol studies were carried out prior to cardiopulmonary bypass surgery for mitral valve surgery. Repeat studies were undertaken 3-4 h and 24-28 h after surgery. Analysis of the rates of pulmonary clearance reproduced the trends seen in earlier research. There was however no statistically significant difference in the variation of serial clearance times between the groups of patients undergoing surgery using the Trillium-coated oxygenators and those using the standard oxygenators.