Ullrich S. Schwertschlag

Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions

Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from skin infiltration by type I T lymphocytes and release of associated cytokines. A multifunctional cytokine, rhIL-11, modulates macrophage and type I T-lymphocyte function in cell culture and shows anti-inflammatory activity in animal models. We are testing subcutaneous delivery of rhIL-11 to patients with psoriasis in a phase 1 open-label dose-escalation clinical trial. Tissue was obtained from lesional and uninvolved skin before and during treatment with rhIL-11 and was examined by histology/immunohistochemistry and quantitative RT-PCR. Expression of over 35 genes was examined in all patients, and multiple genetic markers of psoriasis were identified. Expression of numerous proinflammatory genes was elevated in psoriatic tissue compared with nonlesional skin. Seven of 12 patients responded well to rhIL-11 treatment. Amelioration of disease by rhIL-11, as shown by reduced keratinocyte proliferation and cutaneous inflammation, was associated with decreased expression of products of disease-related genes, including K16, iNOS, IFN-gamma, IL-8, IL-12, TNF-alpha, IL-1beta, and CD8, and with increased expression of endogenous IL-11. We believe that this is the first study in humans to indicate that type I cytokines can be selectively suppressed by an exogenous immune-modifying therapy. The study highlights the utility of pharmacogenomic monitoring to track patient responsiveness and to elucidate anti-inflammatory mechanisms.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease

BACKGROUND & AIMS Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohns disease and to explore the effects of dose and schedule on platelet count and Crohns disease activity. METHODS A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohns disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS Short-term treatment with rhIL-11 is well tolerated in patients with active Crohns disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohns disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling

Psoriasis is recognized as the most common T cell-mediated inflammatory disease in humans. Genetic linkage to as many as six distinct disease loci has been established but the molecular etiology and genetics remain unknown. To begin to identify psoriasis disease-related genes and construct in vivo pathways of the inflammatory process, a genome-wide expression screen of multiple psoriasis patients was undertaken. A comprehensive list of 159 genes that define psoriasis in molecular terms was generated; numerous genes in this set mapped to six different disease-associated loci. To further interpret the functional role of this gene set in the disease process, a longitudinal pharmacogenomic study was initiated to understand how expression levels of these transcripts are altered following patient treatment with therapeutic agents that antagonize calcineurin or NF-κB pathways. Transcript levels for a subset of these 159 genes changed significantly in those patients who responded to therapy and many of the changes preceded clinical improvement. The disease-related gene map provides new insights into the pathogenesis of psoriasis, wound healing and cellular-immune reactions occurring in human skin as well as other T cell-mediated autoimmune diseases. In addition, it provides a set of candidate genes that may serve as novel therapeutic intervention points as well as surrogate and predictive markers of treatment outcome.

Hematopoietic, immunomodulatory and epithelial effects of interleukin-11

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-κB). The block to NF-κB nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-κB, IκB-α and IκB-β. In addition to effects on macrophages, rhIL-11 also reduces CD4+ T cell production of Th1 cytokines, such as IFNγ induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFNγ production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNFα, IFNγ and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn’s disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4+ Th1 cells in conjunction with activated macrophages.

Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease

Interleukin‐11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin‐11 (rhIL‐11) in patients with Crohns disease.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans. All subjects were between the ages of 18 and 45 years, with normal cardiac, hematologic, hepatic, and renal function. Doses of MOX studied were 3, 9, 18, and 36 mg in cohorts of 6 subjects each (5:1, MOX:placebo). At the 9‐mg and 36‐mg doses, two separate cohorts were completed, one in the fasted state and one after the consumption of a high‐fat breakfast. For all other cohorts, administration was in the fasted state. Safety and tolerability were assessed by physical examinations, ongoing evaluation of adverse events (AEs), and measurement of laboratory values. Pharmacokinetic (PK) samples were collected just prior to dosing and at various time points until 80 days postdose. Safety assessments from all dose groups studied suggested that MOX was generally safe and well tolerated, with a slightly higher incidence of transient, mild, and moderate central nervous system AEs as the dose increased as compared to placebo. The PKs of MOX were dose proportional within the dose range studied, and the elimination half‐life (t1/2 elim) was long (mean: 20.2–35.1 days). At the 9‐mg and 36‐mg doses, a high‐fat breakfast was shown to delay and increase the overall absorption but did not increase maximal concentrations when compared to administration in the fasted state. In summary, the results from this study indicate that MOX is safe and well tolerated in humans between the doses of 3 mg and 36 mg.

K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis

Background:  K16, a type I keratin, is upregulated in hyperproliferative states including psoriasis. It has been used as a marker of psoriasis and its expression is upregulated in relapsing psoriasis and downregulating in resolving. We evaluated non‐lesional psoriatic skin for K16 expression.

Multiple‐Dose, Safety, Pharmacokinetics, and Pharmacodynamics of a New Selective Estrogen Receptor Modulator, ERA‐923, in Healthy Postmenopausal Women

ERA‐923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once‐daily oral ERA‐923 (10–200 mg) for 28 days in healthy postmenopausal females. ERA‐923 was well tolerated, and adverse events were mild and reversible. No clinically significant changes in laboratory values were found with ERA‐923 versus placebo. ERA‐923 appeared to undergo extensive metabolism and enterohepatic recirculation. In addition, pharmacokinetic analysis showed that a high‐fat breakfast increased the extent of absorption. ERA‐923‐dosed subjects had no uterine or ovarian changes when evaluated with transvaginal ultrasound and compared to placebo subjects. Overall, ERA‐923 was safe and well tolerated in postmenopausal women dosed for 28 days.

Mechanism and Amelioration of Recombinant Human Interleukin‐11 (rhIL‐11)–Induced Anemia in Healthy Subjects

Recombinant human interleukin‐11 (rhIL‐11), or Neumega® rhIL‐11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti‐inflammatory and immune‐modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL‐11‐induced volume retention and devise a possible therapeutic intervention to ameliorate this effect. Eighteen healthy volunteers (9 male and 9 female) on a controlled sodium (180 mEq/day) and potassium (120 mEq/day) diet were randomized to one of six treatment sequences in a three‐period crossover design. Each subject received 25 μg/kg IL‐11 SC once daily, 25 μg/kg IL‐11 SC once daily + Maxzide‐25® twice daily, or placebo for 7 days in a crossover design. There was a 14‐day washout period between treatment periods. Renal clearance parameters indicated that mean sodium excretion was decreased compared to placebo within 8 hours after dosing with rhIL‐11, with these results reaching statistical significance 8 to 16hourspostdose (p < 0.01). The cumulative sodium excretion (mEq ± SD) over the 7‐day treatment period for each respective treatment group was the following: rhIL‐11 = 833 ± 154, rhIL‐11 + Maxzide‐25® twice daily = 1114 ± 178, and placebo = 982 ± 193 (p < 0.01). Hemoglobin concentration and hematocrit values, used as indicators of hemodilution, decreased in the rhIL‐11‐treated group as compared to the baseline and placebo groups (p < 0.01). Concurrent dosing with Maxzide‐25® twice daily reduced the rhIL‐11‐associated hemodilution by about 50%.

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 μg of recombinant human interleukin‐12 (rhIL‐12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL‐12 were evaluated. Recombinant human IL‐12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu‐like symptoms, which exhibited a dose‐response relationship. Pharmacokinetic analysis suggested that serum IL‐12 levels increased with dose. Analysis of serum levels indicated that interferon‐γ increased with the dose of rhIL‐12, whereas IL‐6 levels showed no changes with rhIL‐12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL‐12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon‐γ and signal transducer and activator of transcription are biomarkers of rhIL‐12 activity.