HYB 2055 – a second-generation immunomodulatory oligonucleotide containing CpR motifs potently reverses allergic airway inflammation and airway hyperresponsiveness in mouse models of established asthma

Abstract

Rationale We have recently reported that second-generation immunomodulatory oligonucleotides (IMOs) containing CpR motifs prevent allergic asthma in mouse models. Since most asthmatics are treated after the development of asthma, we determined whether HYB 2055 can reverse established allergic airway inflammation in mouse models. Methods BALB/c mice sensitized and challenged with ovalbumin were evaluated for airway hyperresponsiveness to methacholine. Following ovalbumin sensitization, mice were randomized and treated with PBS or sc administration of HYB 2055 at two different dose levels during the following 10 days. Two days after the final treatment, mice were rechallenged with ovalbumin and pulmonary functions were recorded. Results HYB 2055 treatment significantly protected ovalbumin-sensitized mice from both early and late allergic response, airway hypersensitivity and hyperreactivity to methacholine compared with a control group of mice treated with PBS. A significant reduction in BAL eosinophilia, BAL and serum IL-5, and total serum IgE was observed in mice treated with HYB 2055 at both doses. Additionally, there was an increase in immature DCs (CD11c+CD45R+) with decrease in DC2 type cells (CD11c+ CD11b+CD8α-) in the lungs of the mice treated with HYB 2055 compared with PBS-treated control animals. Conclusions HYB 2055 is effective and potent in attenuating established allergic airway inflammation in bronchial asthma. The reversal of established asthma following HYB 2055 treatment could be as result of its ability to induce Th1 cytokine secretion, including IL-10, and its effect on decreasing lung DC2 cells and increasing immature DCs. Currently, HYB 2055 is under evaluation for its safety and immunopharmacology in healthy human volunteers.