Abstract
Background: The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as atopic dermatitis. Objective: Given the mass publication of scientific data, an appraisal of safety aspects is challenging. Methods: We here provide a three-fold approach to survey clinically relevant information on off-target effects, both adverse and beneficial, that may potentially be encountered in patients undergoing long-term IL-13 inactivation. First, we review non-clinical data in vivo and in vitro. Second, we summarize safety data accumulating from patients dosed with anti-IL-13 drugs. Third, we exploit human mutation data as well as emerging large-scale genetic datasets (global exome data from 60,000 patients) to obtain information on any association of IL-13-inactivating genetic variants with disease states. In addition, we: (1) dissect the precise efficacy signals obtained with various drugs targeting IL-13 and/or IL-4, and (2) summarize unintended, but potentially beneficial effects of prolonged IL-13 inactivation on several functional systems. Results: Prolonged repression of IL-13 in several thousand patients so far has not uncovered any non-redundant functions of IL-13 in immune defense. Furthermore, missense mutations in the key genes IL-13, IL-13Rα1, IL-13Rα2, IL-4, IL-4Rα are common, while no case reports have been published on any immune deficiency or increased risk of neoplastic disease associated with such mutations, suggesting that these genes do not harbor non-redundant roles in adult outbred humans. In terms of efficacy, data from clinically used drugs strongly suggest that targeting IL-13 only, as opposed to IL-13 and IL-4, may be effective in eczema while being more selective. Importantly, several lines of evidence suggest that inhibition of IL-13 may in fact harbor potentially beneficial effects on non-targeted systems, including glucose metabolism, hepatic fibrosis, and atherosclerosis, suggesting that respective outcomes should be systematically captured in patients dosed with IL-13 interfering drugs. Collectively, available evidence suggests that IL-13 may fulfill safety requirements required for the target of a therapeutic vaccine.
Highlights
The selective inhibition of cytokine function via monoclonal antibodies has revolutionized the treatment of chronic inflammatory conditions
Indirectly via signal transducer and activator of transcription 6 (STAT6) activation [22] and a recent review [19] summarizes evidence suggesting that blocking IL-33/interleukin 13 (IL-13) may be beneficial in the treatment of virus-associated lung disease
A precise understanding of the molecular signaling mechanisms suggests that targeting IL-13, while effective, preserves IL-4 signaling through the type-2 IL-4 receptor which may constitute an important safety benefit regarding immunity, especially to helminth infections
Summary
The selective inhibition of cytokine function via monoclonal antibodies has revolutionized the treatment of chronic inflammatory conditions Despite their phenomenal success, there are some limitations to these drugs, including excessive cost for health care providers, emergence of anti-drug antibodies, and the need for relatively frequent dosing, requiring logistics for shipment and storage of sensitive biological products. The second, and in many ways most informative, data set consists of safety data accumulating in the clinical use of monoclonal antibodies. In this context, three IL-13-targeting drugs are being developed in addition to the IL-4/IL-13 dual-specific drug dupilumab which has already been approved. The purpose here is to highlight that systematic and targeted monitoring of such data in patients undergoing IL-13 blocking antibody treatment is essential and required to gauge the clinical relevance of these data
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have