Antibody bivalency improves antiviral efficacy by inhibiting virion release independently of Fc gamma receptors

Mehmet Sahin; Melissa M Remy; Benedict Fallet; Rami Sommerstein; Marianna Florova; Anna Langner; Katja Klausz; Tobias Straub; Mario Kreutzfeldt; Ingrid Wagner; Cinzia T Schmidt; Pauline Malinge; Giovanni Magistrelli; Shozo Izui; Hanspeter Pircher; J Sjef Verbeek; Doron Merkler; Matthias Peipp; Daniel D Pinschewer

doi:10.1016/j.celrep.2022.110303

Antibody bivalency improves antiviral efficacy by inhibiting virion release independently of Fc gamma receptors

Cell Rep. 2022 Feb 1;38(5):110303. doi: 10.1016/j.celrep.2022.110303.

Authors

Mehmet Sahin¹, Melissa M Remy², Benedict Fallet², Rami Sommerstein³, Marianna Florova¹, Anna Langner⁴, Katja Klausz⁴, Tobias Straub⁵, Mario Kreutzfeldt⁶, Ingrid Wagner⁶, Cinzia T Schmidt⁷, Pauline Malinge⁸, Giovanni Magistrelli⁸, Shozo Izui³, Hanspeter Pircher⁵, J Sjef Verbeek⁹, Doron Merkler⁶, Matthias Peipp⁴, Daniel D Pinschewer¹⁰

Affiliations

¹ Department of Biomedicine - Haus Petersplatz, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland.
² Department of Biomedicine - Haus Petersplatz, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
³ Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
⁴ Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany.
⁵ Institute for Immunology, Department for Medical Microbiology and Hygiene, University Medical Center Freiburg, 79104 Freiburg, Germany.
⁶ Department of Pathology and Immunology, Division of Clinical Pathology, University and University Hospital of Geneva, 1211 Geneva, Switzerland.
⁷ BioEM Lab, Center for Cellular Imaging & Nano Analytics, Biozentrum, University of Basel, Basel, Switzerland.
⁸ Light Chain Bioscience, Novimmune SA, Plan-les-Ouates, Switzerland.
⁹ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan.
¹⁰ Department of Biomedicine - Haus Petersplatz, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. Electronic address: [email protected].

Abstract

Across the animal kingdom, multivalency discriminates antibodies from all other immunoglobulin superfamily members. The evolutionary forces conserving multivalency above other structural hallmarks of antibodies remain, however, incompletely defined. Here, we engineer monovalent either Fc-competent or -deficient antibody formats to investigate mechanisms of protection of neutralizing antibodies (nAbs) and non-neutralizing antibodies (nnAbs) in virus-infected mice. Antibody bivalency enables the tethering of virions to the infected cell surface, inhibits the release of virions in cell culture, and suppresses viral loads in vivo independently of Fc gamma receptor (FcγR) interactions. In return, monovalent antibody formats either do not inhibit virion release and fail to protect in vivo or their protective efficacy is largely FcγR dependent. Protection in mice correlates with virus-release-inhibiting activity of nAb and nnAb rather than with their neutralizing capacity. These observations provide mechanistic insights into the evolutionary conservation of antibody bivalency and help refining correlates of nnAb protection for vaccine development.

Keywords: Fc gamma receptors; antibody bivalency; antiviral protection; humoral immunity; immunoglobulin superfamily; inhibition of virion release; lymphocytic choriomeningitis virus (LCMV); virus budding; virus neutralization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology
Antibodies, Viral / immunology
Antibodies, Viral / pharmacology*
Antiviral Agents / pharmacology*
Epitopes / drug effects
Epitopes / immunology
HIV Antibodies / immunology
HIV Antibodies / pharmacology*
Immunoglobulin G / drug effects
Immunoglobulin G / immunology
Mice
Mice, Inbred C57BL
Receptors, Fc / drug effects*
Receptors, IgG / drug effects
Receptors, IgG / immunology

Substances

Antibodies, Neutralizing
Antibodies, Viral
Antiviral Agents
Epitopes
HIV Antibodies
Immunoglobulin G
Receptors, Fc
Receptors, IgG