A Bispecific, Tetravalent Antibody Targeting Inflammatory and Pruritogenic Pathways in Atopic Dermatitis.

Inhibition of IL-4/IL-13 signaling has dramatically improved the treatment of atopic dermatitis (AD). However, in many patients, clinical responses are slow to develop and remain modest. Indeed, some symptoms of AD are dependent on IL-31, which is only partially reduced by IL-4/IL-13 inhibition.

An engineered T-cell engager with selectivity for high mesothelin-expressing cells and activity in the presence of soluble mesothelin.

Mesothelin (MSLN) is an attractive immuno-oncology target, but the development of MSLN-targeting therapies has been impeded by tumor shedding of soluble MSLN (sMSLN), on-target off-tumor activity, and an immunosuppressive tumor microenvironment. We sought to engineer an antibody-based, MSLN-targeted T-cell engager (αMSLN/αCD3) with enhanced ability to discriminate high MSLN-expressing tumors from normal tissue, and activity in the presence of sMSLN. We also studied the antitumor efficacy of this molecule (NM28-2746) alone and in combination with the multifunctional checkpoint inhibitor/T-cell co-activator NM21-1480 (αPD-L1/α4-1BB).

Engineering of a trispecific tumor-targeted immunotherapy incorporating 4-1BB co-stimulation and PD-L1 blockade.

Co-stimulatory 4-1BB receptors on tumor-infiltrating T cells are a compelling target for overcoming resistance to immune checkpoint inhibitors, but initial clinical studies of 4-1BB agonist mAbs were accompanied by liver toxicity. We sought to engineer a tri-specific antibody-based molecule that stimulates intratumoral 4-1BB and blocks PD-L1/PD-1 signaling without systemic toxicity and with clinically favorable pharmacokinetics. Recombinant fusion proteins were constructed using scMATCH3 technology and humanized antibody single-chain variable fragments against PD-L1, 4-1BB, and human serum albumin.

Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

Background & Aims: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2).

Methods: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 μg twice daily (BID) and 24 μg BID.

Capsule and Sprinkle Formulations of Lubiprostone Are Not Biologically Similar in Patients with Functional Constipation.

Introduction: Lubiprostone capsules are approved for managing three different chronic constipation conditions. A "sprinkle" formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo.

Effects of Lubiprostone, an Intestinal Secretagogue, on Electrolyte Homeostasis in Chronic Idiopathic and Opioid-induced Constipation.

Goals: To assess short-term and long-term effects of lubiprostone, a type-2 chloride channel activator, on electrolyte homeostasis.

Background: Conventional laxatives are associated with electrolyte imbalances. Lubiprostone is a type-2 chloride channel activator approved for treating chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and constipation-predominant irritable bowel syndrome in women.

Efficacy of Lubiprostone for the Treatment of Opioid-Induced Constipation, Analyzed by Opioid Class.

Objectives: To examine the efficacy and safety of lubiprostone for the treatment of opioid-induced constipation (OIC) in patients by opioid class received.

Design: Data were pooled from three phase III, randomized, double-blind, placebo-controlled studies.

Subjects/setting: Adults with chronic noncancer pain receiving opioid therapy for 30 or more days and diagnosed with OIC.

The Cost Effectiveness of Lubiprostone in Chronic Idiopathic Constipation.

Objective: The objective of this study was to evaluate the cost effectiveness of lubiprostone, prucalopride, placebo and immediate referral to secondary care in chronic idiopathic constipation (CIC) in an economic model that was used by the UK National Institute for Health and Care Excellence (NICE) in developing guidance.

Methods: We developed a cohort state-transition model to reflect the treatment pathway in CIC from the UK NHS and personal social services perspective. Time on treatment was determined by a treatment continuation rule using data from an indirect comparison and survival curves fitted to long-term data.

Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation.

Background: Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years.

Penetration of a topically administered anti-tumor necrosis factor alpha antibody fragment into the anterior chamber of the human eye.

Objective: To determine whether topically applied ESBA105, a single-chain antibody fragment against tumor necrosis factor (TNF)-α, could efficiently penetrate into the anterior chamber of the human eye.

Design: Multicenter, interventional cohort study.

Participants: Otherwise healthy patients undergoing cataract surgery (cohorts I-III) or combined cataract surgery and vitrectomy (cohort IV).

Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing the efficacy of bevacizumab, adalimumab, and ESBA105.

Purpose: To compare the relative contribution of VEGF and TNF-alpha in the development of laser-induced choroidal neovascularization (CNV) in monkeys and to exploit the feasibility of topical use of suitable antibody fragments for the prevention of experimental CNV.

Methods: To induce experimental CNV, small high-energy laser spots were used to treat several areas of the macula in the retinas of cynomolgus monkeys according to previously published protocols. To prevent abnormalities, bevacizumab (a potent VEGF inhibitor) and adalimumab or ESBA105 (potent TNF-alpha inhibitors) were given by intravitreal injection 1 week before and 1 week and 3 weeks after laser treatment.

Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNF{alpha} single-chain Fv antibody (ESBA105) designed for local therapeutic use.

Objectives: (1) To show that a single-chain Fv antibody (scFv) against tumour necrosis factor alpha (TNFalpha) (ESBA105) has efficacy comparable to a full length anti-TNFalpha IgG (infliximab); (2) to evaluate whether ESBA105 has all the properties required for the local treatment of arthritis; and (3) to investigate its discriminative tissue penetration properties.

Methods: In vivo efficacy was measured in arthritis of the knee joint induced by the intra-articular injection of recombinant human TNFalpha (rhTNFalpha) in Lewis rats. Cartilage penetration of scFv (ESBA105) and full length IgG (infliximab) were studied in bovine cartilage specimens ex vivo.

Efficient intraocular penetration of topical anti-TNF-alpha single-chain antibody (ESBA105) to anterior and posterior segment without penetration enhancer.

Purpose: This study was designed to characterize ocular penetration pathways of ESBA105, a topically administered single-chain antibody (scFv) against tumor necrosis factor (TNF)-alpha, to the anterior and posterior segment of the eye.

Methods: Fresh enucleated whole eyes and isolated corneas of rabbits mounted in perfusion chambers were used for ex vivo penetration studies. In vivo pharmacokinetics and ocular biodistribution of ESBA105 after intravitreal injection or topical administration as eye drops were investigated in rabbits.

Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNF-alpha single-chain antibody, upon topical administration to the rabbit eye.

Purpose: The purpose of this study was to characterize local distribution and systemic absorption of the tumor necrosis factor (TNF)-alpha inhibitory single-chain antibody fragment (scFv) ESBA105 following topical administration to the eye in vivo.

Methods: Rabbits received ESBA105 as topical eye drops in two dosing regimens. First, pharmacokinetics after the topical route of administration was compared to the intravenous (i.

Antibody-based approaches in Alzheimer's research: safety, pharmacokinetics, metabolism, and analytical tools.

High morbidity, enormous socioeconomic costs, and lack of specific treatments emphasize the importance of research on protective therapies against Alzheimer's disease. The efficacy of anti-amyloid immunization strategies has been demonstrated preclinically, prompting the design of clinical studies. However, the detailed mechanisms of action of therapeutic antibodies, especially their influence on the complex amyloid beta peptide (Abeta) metabolism and various Abeta-equilibria present both within and outside the CNS, are far from being clear.

Loss of metal transcription factor-1 suppresses tumor growth through enhanced matrix deposition.

Metal transcription factor-1 (MTF-1) is a ubiquitous transcriptional regulator and chromatin insulator with roles in cellular stress responses and embryonic development. The studies described herein establish for the first time the involvement of MTF-1 in tumor development. Genetically manipulated ras-transformed mouse embryonic fibroblasts (MEFs), wild-type (MTF-1+/+), or nullizygous for MTF-1 (MTF-1-/-) were used to develop fibrosarcoma tumors.

Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver.

Metal-responsive transcription factor-1 (MTF-1) activates the transcription of metallothionein genes and other target genes in response to heavy metal load and other stresses such as hypoxia and oxidative stress. It also has an essential function during embryogenesis: targeted disruption of Mtf1 in the mouse results in lethal liver degeneration on day 14 of gestation. Here we studied Mtf1 knockout mice at embryonic and adult stages, the latter by means of conditional knockout.

Cell growth selection system to detect extracellular and transmembrane protein interactions.

The interplay among extracellular and cell surface proteins, such as the interactions between ligands and receptors or between antigens and antibodies, is involved in a multitude of physiological and pathological phenomena. In the oxidizing milieu of the secretory pathway in eukaryotic cells, many extracellular proteins build disulfide bonds that significantly contribute to their correct folding and structural stability. Thus, conventional yeast two-hybrid interaction assays, which occur in the reducing intracellular environment, might not be adequate to detect extracellular protein-protein interactions.

History of coronary heart disease.

Coronary heart disease, in the mid-twentieth century has become the most frequently occurring lethal disease. Coronary vessels, that is, coronary arteries tend to develop atherosclerotic plaques already at an early stage. The onset and course of this development has often been a mute one, without pain, rendering thereby the recognition of coronary artery disease difficult--far into the twentieth century.

Medical treatment of myocardial ischemia in coronary artery disease: effect of drug regime and irregular dosing in the CAPE II trial.

Objectives: The Circadian Anti-ischemia Program in Europe (CAPE II) compared the efficacy of amlodipine and diltiazem (Adizem XL) and the combination of amlodipine/atenolol and diltiazem (Adizem XL)/isosorbide 5-mononitrate on exercise and ambulatory myocardial ischemia during regular therapy and after omission of medication.

Background: The optimal medical therapy for ischemia suppression and the impact of irregular dosing using agents with different pharmacologic properties has not been established in patients with coronary disease.

Methods: Patients with > or = 4 ischemic episodes or > or = 20 min of ST segment depression on 72-h electrocardiogram were randomized to amlodipine 10 mg once daily or diltiazem (Adizem XL) 300 mg once daily in a 14-week double-blind randomized multicountry study.

The "metal transcription factor" MTF-1: biological facts and medical implications.

Metallothioneins (MTs) are a class of small, cysteine-rich proteins that have an important function in heavy metal metabolism and detoxification and in the management of various forms of cell stress. Several lines of evidence suggest a role for metallothioneins in therapy resistance of malignant tumours, regulation of blood pressure and protection against some neurological diseases. Basal and heavy metal-induced expression of the stress-inducible metallothionein-I and -II genes and some other stress-regulated genes depends on the zinc-finger transcription factor MTF-1.