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Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential
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 impo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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International Union of Crystallography
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159282/ https://www.ncbi.nlm.nih.gov/pubmed/35647920 http://dx.doi.org/10.1107/S2059798322004132 |
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author | Gutiérrez-Fernández, Javier Javaid, Faiza De Rossi, Giulia Chudasama, Vijay Greenwood, John Moss, Stephen E. Luecke, Hartmut |
author_facet | Gutiérrez-Fernández, Javier Javaid, Faiza De Rossi, Giulia Chudasama, Vijay Greenwood, John Moss, Stephen E. Luecke, Hartmut |
author_sort | Gutiérrez-Fernández, Javier |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9159282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-91592822022-06-17 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 Acta Crystallogr D Struct Biol Research Papers 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. International Union of Crystallography 2022-05-09 /pmc/articles/PMC9159282/ /pubmed/35647920 http://dx.doi.org/10.1107/S2059798322004132 Text en © Javier Gutiérrez-Fernández et al. 2022 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. |
spellingShingle | Research Papers Gutiérrez-Fernández, Javier Javaid, Faiza De Rossi, Giulia Chudasama, Vijay Greenwood, John Moss, Stephen E. Luecke, Hartmut Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title | Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title_full | Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title_fullStr | Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title_full_unstemmed | Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title_short | Structural basis of human LRG1 recognition by Magacizumab, a humanized monoclonal antibody with therapeutic potential |
title_sort | structural basis of human lrg1 recognition by magacizumab, a humanized monoclonal antibody with therapeutic potential |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159282/ https://www.ncbi.nlm.nih.gov/pubmed/35647920 http://dx.doi.org/10.1107/S2059798322004132 |
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