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Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans
Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed bet...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258418/ https://www.ncbi.nlm.nih.gov/pubmed/22023369 http://dx.doi.org/10.1111/j.1365-2443.2011.01552.x |
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author | Mizushima, Tsunehiro Yagi, Hirokazu Takemoto, Emi Shibata-Koyama, Mami Isoda, Yuya Iida, Shigeru Masuda, Kazuhiro Satoh, Mitsuo Kato, Koichi |
author_facet | Mizushima, Tsunehiro Yagi, Hirokazu Takemoto, Emi Shibata-Koyama, Mami Isoda, Yuya Iida, Shigeru Masuda, Kazuhiro Satoh, Mitsuo Kato, Koichi |
author_sort | Mizushima, Tsunehiro |
collection | PubMed |
description | Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N-glycosylation sites. The crystal structure shows that one of the two N-glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N-glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation. |
format | Online Article Text |
id | pubmed-3258418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-32584182012-01-17 Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans Mizushima, Tsunehiro Yagi, Hirokazu Takemoto, Emi Shibata-Koyama, Mami Isoda, Yuya Iida, Shigeru Masuda, Kazuhiro Satoh, Mitsuo Kato, Koichi Genes Cells Original Articles Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N-glycosylation sites. The crystal structure shows that one of the two N-glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N-glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation. Blackwell Publishing Ltd 2011-11 /pmc/articles/PMC3258418/ /pubmed/22023369 http://dx.doi.org/10.1111/j.1365-2443.2011.01552.x Text en Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Articles Mizushima, Tsunehiro Yagi, Hirokazu Takemoto, Emi Shibata-Koyama, Mami Isoda, Yuya Iida, Shigeru Masuda, Kazuhiro Satoh, Mitsuo Kato, Koichi Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title | Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title_full | Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title_fullStr | Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title_full_unstemmed | Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title_short | Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans |
title_sort | structural basis for improved efficacy of therapeutic antibodies on defucosylation of their fc glycans |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258418/ https://www.ncbi.nlm.nih.gov/pubmed/22023369 http://dx.doi.org/10.1111/j.1365-2443.2011.01552.x |
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