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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Viral Immunology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1490515
This article is part of the Research Topic Exploring Antiviral Immune Responses and Therapeutic Strategies Against Human Coronaviruses View all articles

IgG1 versus IgG3: Influence of antibody-specificity and allotypic variance on virus neutralization efficacy

Provisionally accepted
Somanath Kallolimath Somanath Kallolimath 1Lin Sun Lin Sun 1Roman Palt Roman Palt 1Esther Föderl-Höbenreich Esther Föderl-Höbenreich 2Antonia Hermle Antonia Hermle 3Leonie Voss Leonie Voss 3Marina Kleim Marina Kleim 3Falk Nimmerjahn Falk Nimmerjahn 3Johannes S. Gach Johannes S. Gach 4Lauren Hitchcock Lauren Hitchcock 4QIANG CHEN QIANG CHEN 5Stanislav Melnik Stanislav Melnik 1Florian Eminger Florian Eminger 1Anja Lux Anja Lux 3Herta Steinkellner Herta Steinkellner 1*
  • 1 University of Natural Resources and Life Sciences Vienna, Vienna, Austria
  • 2 Diagnostic & Research Institute of Pathology, Medical University of Graz, Graz, Styria, Austria
  • 3 Division of Genetics, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Bavaria, Germany
  • 4 Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Irvine, Orange, California, United States
  • 5 The Biodesign Institute, Arizona State University, Tempe, Arizona, United States

The final, formatted version of the article will be published soon.

    Despite the unique advantages of IgG3 over other IgG subclasses, such as mediating enhanced effector functions and increased flexibility in antigen binding due to a long hinge region, the therapeutic potential of IgG3 remains largely unexplored. This may be attributed to difficulties in recombinant expression and the reduced plasma half-life of most IgG3 allotypes. Here, we report plant expression of two SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) that exhibit high (P5C3) and low (H4) antigen binding. P5C3 and H4-IgG1 mAbs were subclass-switched to IgG3 formats, designed for efficient production and increased PK values, carrying three allotypic variations, referred to as -WT, -H, and -KVH. A total of eight mAbs were produced in glycoengineered plants that synthesize fucose-free complex N-glycans with great homogeneity. Antigen, IgG-FcγR immune complex and complement binding studies demonstrated similar activities of all mAbs. In accordance, P5C3 Abs showed minor alterations in SARS-CoV-2 neutralization (NT) and antibodydependent cell-mediated virus inhibition (ADCVI). Clear functional differences were observed between H4 variants with superior ADCVI and NT potencies of H4 IgG3 H. Our comparative study demonstrates the production of an IgG3 variant carrying an Fc domain with equivalent or enhanced functions compared to IgG3-WT, but with the stability and PK values of IgG1. Our data also demonstrate that both allotypic variability and antibody specificity are important for fine-tuning of activities, an important information for the development of future therapeutics.

    Keywords: IgG3 allotypes, Plant expression, SARS-CoV-2 antibodies, Functional activities, Antibody engineering

    Received: 03 Sep 2024; Accepted: 08 Oct 2024.

    Copyright: © 2024 Kallolimath, Sun, Palt, Föderl-Höbenreich, Hermle, Voss, Kleim, Nimmerjahn, Gach, Hitchcock, CHEN, Melnik, Eminger, Lux and Steinkellner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Herta Steinkellner, University of Natural Resources and Life Sciences Vienna, Vienna, Austria

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.