An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

Abstract

Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug.

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

“…The clinical trial studies are need to learn more about the BIO-1211 role in MS treatment. The future of leukocyte integrin antagonist therapy is exciting, promising a new class of therapeutics with the potential to impact not only autoimmune disease but also a broad spectrum of human diseases (Kenyon et al, 2009;Paskowitz et al, 2012;Vanderslice et al, 2010;Yonekawa & Harlan, 2005;). Some functional limitations of therapeutic antibodies have come to light, such as inadequate pharmacokinetics and tissue accessibility as well as impaired interactions with the immune system, and these deficiencies point to areas where additional research is needed (Chames et al, 2009).…”

Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4β1–Expressing Immune Cells

“…Consequently, much of our understanding of TB comes from animal and cell culture models that may not fully model human pathology, or from biopsied human samples that represent the end result of severe pathology. To address questions regarding granuloma development, we used 64 Cu-LLP2A, a peptidomimetic ligand of integrin α4β1 (25, 35), in conjunction with 18 F-FDG, a commonly used PET agent, to study novel aspects of TB in cynomolgus macaques. The presentation of TB in macaques is very similar to human TB, including the extent of lung and lymph node involvement.…”

“…VLA-4 has been targeted by PET imaging with the Cu-64-labeled high affinity peptidomimetic ligand CB-TE1A1P-PEG 4 -LLP2A (hereafter referred to as 64 Cu-LLP2A), which was demonstrated to be taken up in a VLA-4-positive murine melanoma model (23). VLA-4 plays an important role in lymphocyte differentiation and trafficking (24) and there is increasing interest in it as a therapeutic target because of its immunomodulatory activities (25, 26). In Mtb infections, VLA-4-expressing mucosal associated T (MAIT) cells provide some protection in murine TB (27).…”

PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring

“…Pulmonary function was measured using a plethysmograph for restrained animals (Buxco, Troy, NY), with the rat in the supine position. Dynamic compliance and resistance of the respiratory system were simultaneously measured on the anesthetized, tracheotomized, and ventilated rats at baseline and immediately following serial 3-min nebulizations of saline and methacholine (MCh, 0.5 and 2.0 mg/ml), with 3-min recovery periods allowed after each exposure to MCh, as previously described (22,54). The pups were deeply anesthetized and sedated with medetomidine (0.5 mg/kg; Domitor, Orion Pharma) and tiletamine-zolazepam (50 mg/kg; Telazol, Fort Dodge Laboratories, Overland Park, KS) and then ventilated at 7-8 ml/kg with a small animal ventilator (MiniVent, Harvard Apparatus, Cambridge, MA) for the duration of the procedure.…”