Abstract
Interleukin-13 (IL-13) is associated with allergic airway inflammation and airway remodeling. Our group found a variant with a single nucleotide polymorphism in the IL13 gene at position +2044G>A (rs20541) that was expected to result in the non-conservative replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 144. IL-13Q144 was associated with augmented allergic airway inflammation and bronchial asthma remodeling. There is some indication that anti-IL-13 monoclonal antibodies can demonstrate a positive effect on the clinical course of refractory asthmatic patients. To date, the binding stability of these agents for IL-13Q144 is unknown. The objective of this study was to investigate the prediction efficacy of the anti-IL-13 monoclonal antibodies tralokinumab and lebrikizumab in asthmatic patients with IL-13R144 and IL-13Q144. The three-dimensional (3-D) structure of tralokinumab was obtained from the Protein Data Bank (PDB ID: 5L6Y), and the complete 3-D structure of lebrikizumab was built through homology modeling. For the binding stability analysis, we performed and analyzed docking simulations of IL-13 with tralokinumab or lebrikizumab. The tralokinumab and lebrikizumab structures changed after binding to IL-13 to facilitate binding with IL-13Q144. The stability analysis with tralokinumab and lebrikizumab demonstrated that IL-13Q144 was more stable than IL-13R144 for both the Rosetta energy score and for the free energy of binding. IL-13Q144 might be a promising predictor of responsiveness to tralokinumab and lebrikizumab treatment for bronchial asthma.
Highlights
Bronchial asthma is a disorder of the conducting airways, which leads to variable airflow obstructions in association with airway hyper responsiveness and a local accumulation of inflammatory cells, eosinophils, mast cells, and T lymphocytes [1]
We identified the 3-D structures of tralokinumab, lebrikizumab, IL-13R144, and IL-13Q144
We demonstrated that the binding of tralokinumab and lebrikizumab with IL-13Q144 was more stable than the binding with IL-13R144
Summary
Bronchial asthma is a disorder of the conducting airways, which leads to variable airflow obstructions in association with airway hyper responsiveness and a local accumulation of inflammatory cells, eosinophils, mast cells, and T lymphocytes [1]. Docking analysis of an anti-IL-13 antibody corticosteroids (ICSs) are the primary medication used to treat bronchial asthma, based on the efficacy of a strong anti-allergic agent on the inflammatory cells and induced mediators [2,3]. Th2-type cytokines, interleukin-13 (IL-13), have been shown to orchestrate airway allergic inflammatory and remodeling processes [5,6,7], and anti-IL-13 agents have been highlighted for the treatment of asthma cases unresponsive to ICSs. Several clinical trials with biological agents against IL-13 have been conducted and have shown remarkable efficacy [8,9]. The clinical efficacy of anti-IL-13 antibodies may be influenced by the binding affinities of the antibodies to IL-13 and the molecular mechanisms through which they block IL-13 signaling. We analyzed the IL-13 variant based on the binding stability of the anti-IL-13 antibodies tralokinumab and lebrikizumab
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
