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Immunoglobulin interface redesigning to enhance lebrikizumab mediated immunomodulation of IL-13 hyper-response. | LitMetric

AI Article Synopsis

  • The overexpression of interleukin-13 (IL-13) is linked to autoimmune and inflammatory diseases, which can be treated using lebrikizumab, a therapeutic monoclonal antibody.
  • Researchers aimed to improve lebrikizumab’s binding strength to IL-13 by identifying critical interface residues and creating a mutant library through various bioinformatics tools.
  • The best two modified antibody mutants were confirmed to have enhanced binding and stability through molecular dynamics simulations, indicating potential for future IL-13 disease treatments.

Article Abstract

The overexpression of interleukin-13 (IL-13) leads to autoimmune and inflammatory diseases. These adverse responses can be neutralized by using lebrikizumab as a therapeutic monoclonal antibody (mAb). Herein, we have attempted to modulate the lebrikizumab mAb to enhance its binding affinity towards IL-13. The interface residues of the lebrikizumab-IL-13 complex were determined by the PyMOL and verified by the artificial neural network-based B-cell epitope prediction server (ABCpred server) and the Paratome web server. The Cologne University Protein Stability Analysis Tool (CUPSAT) web server based mutational approach was used to identify the stable and favorable interface mutations in the lebrikizumab. Only 40 mutations were selected to generate a single mutant library, and their binding affinity for IL-13 was analyzed by using the Z-Dock server. Based on high Z-score, mutants having a better affinity with IL-13 were selected to create a multi-mutant library. The multi-mutant library was again subjected to the Z-Dock server, and their binding affinity was determined. The highest-scoring ten mAb mutants were validated by using PatchDock and ClusPro servers. The best two potential mAb mutants were identified and subjected to molecular dynamics (MD) simulations to ensure its structural stability at the microscopic level. The changes in the different bonds as the effect of mutation were assessed by LigPlot + v2.1. The AllerTOP and ToxinPred web servers were used to analyze the non-allergic and nontoxic nature of the selected mutants. Therefore, these redesigned mAb could be used for potential treatment against IL-13 associated diseased conditions.Communicated by Ramaswamy H. Sarma.

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http://dx.doi.org/10.1080/07391102.2020.1773316DOI Listing

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