Monoclonal antibodies for the treatment of asthma

The Use of Mouse Asthma Models to Successfully Discover and Develop Novel Drugs

“…Data have accumulated from experiments with congenic, gene-deficient, or transgenic animals and generated a solid knowledge base on the development of asthma as well as therapeutic interventions aimed at preventing disease onset and reducing disease progression [1]. Mechanistic insights gleaned from animal models are important because of the extrapolation potential for human disease [2,3,4], and mouse models, in particular, have led to the discovery of numerous novel targets for the treatment of asthma [2,4,5]. However, despite a myriad of potential drug targets, only anti-IgE monoclonal antibody (mAb) therapy (omalizumab) and, recently, an anti-IL-5 mAb (mepolizumab [6]) have made it to the market [5,7,8,9].…”

“…Mechanistic insights gleaned from animal models are important because of the extrapolation potential for human disease [2,3,4], and mouse models, in particular, have led to the discovery of numerous novel targets for the treatment of asthma [2,4,5]. However, despite a myriad of potential drug targets, only anti-IgE monoclonal antibody (mAb) therapy (omalizumab) and, recently, an anti-IL-5 mAb (mepolizumab [6]) have made it to the market [5,7,8,9]. Additionally, anti-IL-4ra (dupilumab [10]), and anti-IL-13 (lebrikizumab) treatments have also been effective in phase II trials for selected patients with high eosinophilia and/or high periostin serum levels, respectively [4,5,7,9,11].…”

“…However, despite a myriad of potential drug targets, only anti-IgE monoclonal antibody (mAb) therapy (omalizumab) and, recently, an anti-IL-5 mAb (mepolizumab [6]) have made it to the market [5,7,8,9]. Additionally, anti-IL-4ra (dupilumab [10]), and anti-IL-13 (lebrikizumab) treatments have also been effective in phase II trials for selected patients with high eosinophilia and/or high periostin serum levels, respectively [4,5,7,9,11]. Unfortunately, many “proof of concept (POC)” targets derived from preclinical studies on mouse models failed when they were tested in patients, including anti-CCR3 antagonists, anti-IL-17, anti-IL-4, anti-OX40L, anti-TNF-α, anti-IL-1β, PDE 4 inhibitors, and TLR agonists, amongst numerous others [5,12,13].…”

“…Additionally, anti-IL-4ra (dupilumab [10]), and anti-IL-13 (lebrikizumab) treatments have also been effective in phase II trials for selected patients with high eosinophilia and/or high periostin serum levels, respectively [4,5,7,9,11]. Unfortunately, many “proof of concept (POC)” targets derived from preclinical studies on mouse models failed when they were tested in patients, including anti-CCR3 antagonists, anti-IL-17, anti-IL-4, anti-OX40L, anti-TNF-α, anti-IL-1β, PDE 4 inhibitors, and TLR agonists, amongst numerous others [5,12,13]. Notably, the failure of many drug candidates was not because they were ineffective, but because they were not any more effective than the current standard therapeutics.…”

Controversies Surrounding the Potential Use of Histone Deacetylase Inhibitors for the Treatment of Asthma

“…Firstly, antileukotrienes including the leukotriene receptor antagonists, zafirlukast (Accolate) and montelukast (Singulair) and the 5-lipoxygenase inhibitor zileuton (Zyflo) have been approved for the treatment of asthma [20][21][22][23][24][25]. Another approach involves the investigation of anti-inflammatory antibodies, which have included clinical trials withanti-IL-5, IL-4, IL-13, TNFα, CCR3, CCR4, and OX40L [26,27]. To date, the anti-IgE monoclonal antibody, omalizumab (Xolair), has been approved; for the treatment of moderateto-severe adult and childhood asthma by the US Food and Drug Administration (FDA) in 2003 [28][29][30].…”