These agents include therapeutics that target IL-4 (altrakincept), IL-13 (lebrikizumab, GSK67586, IMA-638, IMA-026, tralokinumab), IL-4Rα (dupilumab, AMG-317, pitrakinra), and membrane IgE (quilizumab). In reviewing the clinical data, it should be OSI-744 mw noted that differences in the effects of these therapeutic agents on IgE production may result from differences in the potencies of the various therapeutics against their respective targets, differences in therapeutic exposure due to different routes of administration and/or dosing frequencies, as well as differences in the

characteristics of the patient cohorts in each clinical study. The effect of neutralizing IL-13 and/or IL-4 on IgE production in humans has been assessed in a number of different clinical studies. Treatment with lebrikizumab, an anti-IL-13 monoclonal antibody, reduced total serum IgE levels by approximately 20% in patients with asthma [45•, 46 and 47]. In these studies, proximal biomarkers of IL-13 blockade (e.g.

FeNO and CCL17) revealed near-maximal inhibition of IL-13 activity following a single dose, whereas serum IgE levels declined more slowly during the 3–6 month treatment period. Since the half-life of serum IgE in humans is very short (approximately 1–2 days), these results are consistent with a slow decline Methane monooxygenase in serum IgE upon the turnover of short-lived IgE plasma cells downstream of the inhibition HDAC inhibitor of IL-13-induced IgE class switching. These studies also suggest that at least 20% of total serum IgE in these patients was generated from ongoing IgE B cell responses (which can be driven by both IL-4 and IL-13). By contrast, the anti-IL-13 monoclonal antibodies IMA-638, IMA-026, and GSK67586 failed to demonstrate effects on serum IgE in clinical studies [48 and 49], but differences in antibody potencies, antibody exposure, and/or clinical study design may have contributed to the lack of effect as compared

to lebrikizumab. The contribution of IL-4 to IgE production in patients with asthma is less clear. Blockade of IL-4 using a soluble recombinant IL-4Rα protein (altrakincept) did not result in reductions in serum IgE, although this therapeutic was delivered via nebulization and therefore would have had only local effects in the lung, with very little systemic activity [50]. Similarly, blockade of both IL-4 and IL-13 using a nebulized variant IL-4 protein that binds to IL-4Rα but does not activate signaling (pitrakinra) did not have any effect on serum IgE [51]. By contrast, blockade of both IL-4 and IL-13 using monoclonal antibodies against IL-4Rα (AMG-317 and dupilumab) administered subcutaneously reduced total serum IgE levels [52• and 53•].