4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis.

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  • Additional Information
    • Source:
      Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Research Foundation]
    • Subject Terms:
      Antibodies, Antineutrophil Cytoplasmic/*immunology ; Antibodies, Monoclonal/*immunology ; B-Lymphocytes/*immunology ; Granulomatosis with Polyangiitis/*immunology ; Myeloblastin/*immunology; Aged ; Antibodies, Antineutrophil Cytoplasmic/metabolism ; Antibodies, Monoclonal/metabolism ; Antibody Affinity ; Antibody Specificity ; B-Lymphocytes/enzymology ; Binding Sites, Antibody ; Biomarkers/metabolism ; Case-Control Studies ; Cell Line ; Epitope Mapping ; Epitopes ; Female ; Glycosylation ; Granulomatosis with Polyangiitis/diagnosis ; Granulomatosis with Polyangiitis/enzymology ; Humans ; Male ; Middle Aged ; Neutrophil Activation ; Proof of Concept Study
    • Abstract:
      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.
      (Copyright © 2020 Granel, Lemoine, Morello, Gallais, Mariot, Drapeau, Musnier, Poupon, Pugnière, Seren, Nouar, Gouilleux-Gruart, Watier, Korkmaz and Hoarau.)
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    • Contributed Indexing:
      Keywords: anti-neutrophil cytoplasmic antibodies; epitope; granulomatosis with polyangiitis; human neutrophils; proteinase 3
    • Accession Number:
      0 (Antibodies, Antineutrophil Cytoplasmic)
      0 (Antibodies, Monoclonal)
      0 (Biomarkers)
      0 (Epitopes)
      EC 3.4.21.76 (Myeloblastin)
    • Publication Date:
      Date Created: 20201026 Date Completed: 20210614 Latest Revision: 20210614
    • Publication Date:
      20221213
    • Accession Number:
      PMC7546423
    • Accession Number:
      10.3389/fimmu.2020.573040
    • Accession Number:
      33101296