Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases

Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicit...

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Autores principales: Pierri, Ciro Leonardo, Bossis, Fabrizio, Punzi, Giuseppe, De Grassi, Anna, Cetrone, Michela, Parisi, Giovanni, Tricarico, Domenico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777268/
https://www.ncbi.nlm.nih.gov/pubmed/26977294
http://dx.doi.org/10.1002/prp2.197
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author Pierri, Ciro Leonardo
Bossis, Fabrizio
Punzi, Giuseppe
De Grassi, Anna
Cetrone, Michela
Parisi, Giovanni
Tricarico, Domenico
author_facet Pierri, Ciro Leonardo
Bossis, Fabrizio
Punzi, Giuseppe
De Grassi, Anna
Cetrone, Michela
Parisi, Giovanni
Tricarico, Domenico
author_sort Pierri, Ciro Leonardo
collection PubMed
description Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.
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spelling pubmed-47772682016-03-14 Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases Pierri, Ciro Leonardo Bossis, Fabrizio Punzi, Giuseppe De Grassi, Anna Cetrone, Michela Parisi, Giovanni Tricarico, Domenico Pharmacol Res Perspect Original Articles Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions. John Wiley and Sons Inc. 2016-01-15 /pmc/articles/PMC4777268/ /pubmed/26977294 http://dx.doi.org/10.1002/prp2.197 Text en © 2016 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Pierri, Ciro Leonardo
Bossis, Fabrizio
Punzi, Giuseppe
De Grassi, Anna
Cetrone, Michela
Parisi, Giovanni
Tricarico, Domenico
Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title_full Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title_fullStr Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title_full_unstemmed Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title_short Molecular modeling of antibodies for the treatment of TNF α‐related immunological diseases
title_sort molecular modeling of antibodies for the treatment of tnf α‐related immunological diseases
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777268/
https://www.ncbi.nlm.nih.gov/pubmed/26977294
http://dx.doi.org/10.1002/prp2.197
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