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

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

doi:10.1016/j.celrep.2022.110303

Abstract

SummaryAcross 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.

Highlights

Antibody responses constitute a key element of antiviral adaptive immunity and, with the recent advancements in the field of molecular engineering, antibodies have become a key therapeutic modality for a wide array of diseases (Winter, 2019)
Antibodies belong to the immunoglobulin superfamily, a large class of cell surface molecules and soluble proteins that are involved in binding, adhesion, and recognition processes of cells, the latter prominently represented by the hypervariable T cell and B cell receptors
Our observations suggest bivalency-dependent inhibition of virion release as an archetypical and highly conserved antiviral effector mechanism, which may account for a substantial proportion of neutralizing antibodies (nnAbs) and even neutralizing antibodies (nAbs) efficacy

Summary

Introduction

Antibody responses constitute a key element of antiviral adaptive immunity and, with the recent advancements in the field of molecular engineering, antibodies have become a key therapeutic modality for a wide array of diseases (Winter, 2019). These include viral infections of global significance, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and respiratory syncytial virus (Abraham, 2020; Cao et al, 2020; Englund, 1999; Soto et al, 2020), rendering it important to better understand how antiviral antibodies protect in vivo.

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