Marilyn C. Pike

Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study

Objective To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE). Methods A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37–39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA). Results Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels. Conclusions Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing.

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double-Blind, Placebo-Controlled Trials

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results from the Phase 3, Randomized, Double-blind, Placebo-controlled Trials, EMBODY™ 1 and EMBODY™ 2.

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

GRO: A Novel Chemotactic Cytokine

Cytokines are small secreted regulatory peptides that act primarily in a paracrine fashion to provide a signalling system between different cell types. Although cytokine functions were initially associated with myeloid and lymphocytic responses to infection, current studies are demonstrating regulatory functions in growth and differentiation as well. Our studies with the GRO gene represent one of the first to describe a novel cytokine expressed by fibroblasts and epithelial cells as well as cells of the immune system, with regulatory functions both in growth and in the inflammatory response (1, 2, 3).

Long‐Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate‐to‐ Severe Systemic Lupus Erythematosus: Results From an Open‐Label Extension Study

The primary objective was to assess the long‐term safety of repeated courses of epratuzumab therapy in patients with moderate‐to‐severe systemic lupus erythematosus. Secondary objectives were to assess long‐term efficacy and health‐related quality of life (HRQOL).

Characterization of interleukin-8 receptors in human neutrophil membranes: Regulation by guanine nucleotides

Interleukin-8 (IL-8) is a polymorphonuclear leukocyte (PMN) chemoattractant and activator which mediates its effects through specific cell-surface receptors. Indirect evidence indicates that guanine nucleotide regulatory proteins (G proteins) are necessary for transmembrane signaling. The present study characterizes IL-8 receptors in isolated PMN membrane fractions and shows direct regulation of these receptors by guanine nucleotides. The binding of [125I]IL-8 to subcellular fractions of PMNs showed specific binding in a low-density membrane fraction containing alkaline phosphatase, but not in primary or secondary granules. The binding of [125I]IL-8 was rapid and reversible. The equilibrium dissociation constant (Kd) of the receptor ranged from 5.0-12.4 nM and there were 1.58-5.90 . 10(10) receptors/mg protein. The dose-response curves for the competitive binding of three different forms of IL-8 to the receptor labeled by [125I]IL-8 corresponded with their ability to produce chemotaxis and granule exocytosis in PMNs. Treatment of membranes with the nonhydrolyzable analogs of GTP, GMP-PNP and GTP gamma S, inhibited the binding of [125I]IL-8. GMP-PNP decreased the affinity of the IL-8 receptor by approx. 2-fold without altering the total receptor number. These findings demonstrate that IL-8 receptors in PMN membranes are of high affinity and are convertible to a low-affinity state in the presence of guanine nucleotides, suggesting a direct role for G proteins in transmembrane signaling by this cytokine.

Data Quality Challenges in Systemic Lupus Erythematosus Trials: How Can This Be Optimized?

Major scientific advances in basic science, pharmacology, and translational medicine have allowed the discovery of new molecular targets whose manipulation by new chemical entities has led to treatments for inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Development of new agents for systemic lupus erythematosus (SLE) has lagged, however, because the protean manifestations of SLE present challenges for measuring therapeutic effects in a consistent manner. Composite end points combining several Disease Activity Indices (DAIs) are being used in ongoing global studies, but the uniform application of these complex DAIs across large numbers of clinical sites has proven difficult. We describe herein approaches that are being utilized to facilitate collection, review, and analysis of the clinical measures utilizing independent central adjudication committees.

Chapter 2 Chemoattractant Receptors as Regulators of Phagocytic Cell Function

Publisher Summary This chapter discusses the physiological and biochemical parameters of the most thoroughly described chemo-attractant receptors whose physiology may provide a molecular basis for these complex functions of inflammatory cells. Chemoattractants mediate not only the directed migration of leukocytes but also induce a series of coordinated biochemical events, including ion fluxes, cytoskeletal rearrangements associated with morphological polarization, changes in lipid metabolism, activation of protein kinases, production of superoxide anion, and release of lysosomal enzymes. Chemo-attractant-mediated biological and biochemical responses can be divided into two major categories: those functions and biochemical processes that are triggered by the low concentrations of chemoattractants, such as cellular migration, and functions, such as activation of the oxidative burst associated with 10- to 100-fold higher concentrations of chemotactic factors. Advances have been made in the study of leukocyte chemo-attractant receptors mainly because of the availability of large numbers of single-cell suspensions of leukocytes from either peripheral blood or peritoneal exudates as well as the availability of stable, high-affinity, highly purified, radioactive ligands.

The Role of the Neutrophil in the Inflammatory Response

In the latter part of the nineteenth century, Metchnikoff observed the localization of amebocytes around a rose thorn that had penetrated into the coelomic cavity of a transparent starfish larva. He was struck by the “walling off” or engulfment of foreign particles by these motile cells. Based on these and other findings, Metchnikoff (1891) proposed a major role for phagocytic cells in mediating resistance to microbial invasion. The immune system is now known to consist of humoral and cellular components whose complex interactions can protect against microbial invasion and the development and spread of neoplasms. The immunologic recognition of foreign substances results in the production of inflammatory mediators through the activation of enzyme cascade systems such as complement and by the release of soluble products from leukocytes (i.e., lymphokines and arachidonic acid metabolites) (Cohen et al., 1979; Gallin and Quie, 1978; Kuehl and Egan, 1980; Snyderman, 1982). These mediators recruit phagocytes and lymphocytes to sites of immune reactions. Polymorphonuclear leukocytes (PMN) and macrophages are phagocytic cells whose functions are required for the actual degradation of antigens.