IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy
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...
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Frontiers Media S.A.
2024-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1490515/full |
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| author | Somanath Kallolimath Lin Sun Roman Palt Esther Föderl-Höbenreich Antonia Hermle Leonie Voss Marina Kleim Falk Nimmerjahn Falk Nimmerjahn Johannes S. Gach Lauren Hitchcock Qiang Chen Stanislav Melnik Florian Eminger Anja Lux Anja Lux Herta Steinkellner |
| author_facet | Somanath Kallolimath Lin Sun Roman Palt Esther Föderl-Höbenreich Antonia Hermle Leonie Voss Marina Kleim Falk Nimmerjahn Falk Nimmerjahn Johannes S. Gach Lauren Hitchcock Qiang Chen Stanislav Melnik Florian Eminger Anja Lux Anja Lux Herta Steinkellner |
| author_sort | Somanath Kallolimath |
| collection | DOAJ |
| description | 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 antibody-dependent 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. |
| format | Article |
| id | doaj-art-a923dba30332487ea742f0b863b2b29e |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-a923dba30332487ea742f0b863b2b29e2025-08-20T01:54:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-10-011510.3389/fimmu.2024.14905151490515IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacySomanath Kallolimath0Lin Sun1Roman Palt2Esther Föderl-Höbenreich3Antonia Hermle4Leonie Voss5Marina Kleim6Falk Nimmerjahn7Falk Nimmerjahn8Johannes S. Gach9Lauren Hitchcock10Qiang Chen11Stanislav Melnik12Florian Eminger13Anja Lux14Anja Lux15Herta Steinkellner16Institute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaDiagnostic and Research Institute of Pathology, Medical University of Graz, Graz, AustriaDivision of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDivision of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDivision of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDivision of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyFAU Profile Centre Immunomedicine, Erlangen, GermanyDivision of Infectious Diseases, University of California, Irvine, Irvine, CA, United StatesDivision of Infectious Diseases, University of California, Irvine, Irvine, CA, United StatesThe Bio design Institute and School of Life Sciences, Arizona State University, Tempe, AZ, United StatesInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaDivision of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyFAU Profile Centre Immunomedicine, Erlangen, GermanyInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, BOKU University, Vienna, AustriaDespite 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 antibody-dependent 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1490515/fullIgG3 allotypesplant expressionSARS-CoV-2 antibodiesfunctional activitiesantibody engineering |
| spellingShingle | Somanath Kallolimath Lin Sun Roman Palt Esther Föderl-Höbenreich Antonia Hermle Leonie Voss Marina Kleim Falk Nimmerjahn Falk Nimmerjahn Johannes S. Gach Lauren Hitchcock Qiang Chen Stanislav Melnik Florian Eminger Anja Lux Anja Lux Herta Steinkellner IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy Frontiers in Immunology IgG3 allotypes plant expression SARS-CoV-2 antibodies functional activities antibody engineering |
| title | IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy |
| title_full | IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy |
| title_fullStr | IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy |
| title_full_unstemmed | IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy |
| title_short | IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy |
| title_sort | igg1 versus igg3 influence of antibody specificity and allotypic variance on virus neutralization efficacy |
| topic | IgG3 allotypes plant expression SARS-CoV-2 antibodies functional activities antibody engineering |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1490515/full |
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