4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis
Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase. PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune...
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| Format: | Article |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.573040/full |
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| author | Jérôme Granel Jérôme Granel Roxane Lemoine Eric Morello Yann Gallais Julie Mariot Marion Drapeau Astrid Musnier Anne Poupon Martine Pugnière Seda Seren Seda Seren Dalila Nouar Valérie Gouilleux-Gruart Valérie Gouilleux-Gruart Hervé Watier Hervé Watier Brice Korkmaz Brice Korkmaz Cyrille Hoarau Cyrille Hoarau |
| author_facet | Jérôme Granel Jérôme Granel Roxane Lemoine Eric Morello Yann Gallais Julie Mariot Marion Drapeau Astrid Musnier Anne Poupon Martine Pugnière Seda Seren Seda Seren Dalila Nouar Valérie Gouilleux-Gruart Valérie Gouilleux-Gruart Hervé Watier Hervé Watier Brice Korkmaz Brice Korkmaz Cyrille Hoarau Cyrille Hoarau |
| author_sort | Jérôme Granel |
| collection | DOAJ |
| description | Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase. PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κ anti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic. This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA. |
| first_indexed | 2024-12-14T02:24:46Z |
| format | Article |
| id | doaj.art-7c2203b277ea43dd8313ce7bf3093377 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T02:24:46Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7c2203b277ea43dd8313ce7bf30933772022-12-21T23:20:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-09-011110.3389/fimmu.2020.5730405730404C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With PolyangiitisJérôme Granel0Jérôme Granel1Roxane Lemoine2Eric Morello3Yann Gallais4Julie Mariot5Marion Drapeau6Astrid Musnier7Anne Poupon8Martine Pugnière9Seda Seren10Seda Seren11Dalila Nouar12Valérie Gouilleux-Gruart13Valérie Gouilleux-Gruart14Hervé Watier15Hervé Watier16Brice Korkmaz17Brice Korkmaz18Cyrille Hoarau19Cyrille Hoarau20Plateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FranceService transversal d’Immunologie Clinique et d’Allergologie, Centre Hospitalier Régional Universitaire, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FranceMAbSilico SAS, Domaine de l’Orfasière, Nouzilly, FrancePhysiologie de la Reproduction et des Comportements, INRA UMR 0085, CNRS UMR 7247, Université de Tours, Tours, FranceInstitut de Recherche en Cancérologie, Institut Régional du Cancer, INSERM U1194, Université Montpellier, Montpellier, FranceCentre d’Etude des Pathologies Respiratoires, INSERM, UMR 1100, Tours, FranceUniversité de Tours, Tours, FranceService transversal d’Immunologie Clinique et d’Allergologie, Centre Hospitalier Régional Universitaire, Tours, FranceUniversité de Tours, Tours, FranceLaboratoire d’Immunologie, Centre Hospitalier Régional Universitaire, Tours, FranceUniversité de Tours, Tours, FranceLaboratoire d’Immunologie, Centre Hospitalier Régional Universitaire, Tours, FranceCentre d’Etude des Pathologies Respiratoires, INSERM, UMR 1100, Tours, FranceUniversité de Tours, Tours, FrancePlateforme B Cell Ressources (BCR) EA4245, Université de Tours, Tours, FranceService transversal d’Immunologie Clinique et d’Allergologie, Centre Hospitalier Régional Universitaire, Tours, FranceGranulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase. PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κ anti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic. This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA.https://www.frontiersin.org/article/10.3389/fimmu.2020.573040/fullanti-neutrophil cytoplasmic antibodiesproteinase 3granulomatosis with polyangiitisepitopehuman neutrophils |
| spellingShingle | Jérôme Granel Jérôme Granel Roxane Lemoine Eric Morello Yann Gallais Julie Mariot Marion Drapeau Astrid Musnier Anne Poupon Martine Pugnière Seda Seren Seda Seren Dalila Nouar Valérie Gouilleux-Gruart Valérie Gouilleux-Gruart Hervé Watier Hervé Watier Brice Korkmaz Brice Korkmaz Cyrille Hoarau Cyrille Hoarau 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis Frontiers in Immunology anti-neutrophil cytoplasmic antibodies proteinase 3 granulomatosis with polyangiitis epitope human neutrophils |
| title | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| title_full | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| title_fullStr | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| title_full_unstemmed | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| title_short | 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis |
| title_sort | 4c3 human monoclonal antibody a proof of concept for non pathogenic proteinase 3 anti neutrophil cytoplasmic antibodies in granulomatosis with polyangiitis |
| topic | anti-neutrophil cytoplasmic antibodies proteinase 3 granulomatosis with polyangiitis epitope human neutrophils |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.573040/full |
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