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Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential

Gutiérrez-Fernández, Javier; Javaid, Faiza; De Rossi, Giulia; Chudasama, Vijay; Greenwood, John; Moss, Stephen E; Luecke, Hartmut; (2022) Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential. Acta Crystallographica Section D Structural Biology , 78 (6) 10.1107/s2059798322004132. Green open access

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Abstract

The formation of new dysfunctional blood vessels is a crucial stage in the development of various conditions such as macular degeneration, diabetes, cardiovascular disease, neurological disease and inflammatory disorders, as well as during tumor growth, eventually contributing to metastasis. An important factor involved in pathogenic angiogenesis is leucine-rich α-2-glycoprotein 1 (LRG1), the antibody blockade of which has been shown to lead to a reduction in both choroidal neovascularization and tumor growth in mouse models. In this work, the structural interactions between the LRG1 epitope and the Fab fragment of Magacizumab, a humanized function-blocking IgG4 against LRG1, are analysed, determining its specific binding mode and the key residues involved in LRG1 recognition. Based on these structural findings, a series of mutations are suggested that could be introduced into Magacizumab to increase its affinity for LRG1, as well as a model of the entire Fab–LRG1 complex that could enlighten new strategies to enhance affinity, consequently leading towards an even more efficient therapeutic.

Type: Article
Title: Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential
Open access status: An open access version is available from UCL Discovery
DOI: 10.1107/s2059798322004132
Publisher version: https://doi.org/10.1107/S2059798322004132
Language: English
Additional information: https://creativecommons.org/licences/by/4.0/legalcode This is an open access article under the CC BY 4.0 license Attribution 4.0 International
Keywords: cancer immunotherapy; leucine-rich α-2-glycoprotein 1; Magacizumab; angiogenesis; antibody–antigen complex
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10148597
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