First Infusion Reactions are Mediated by Fc\u03b3RIIIb and Neutrophils

Felix Weber,Claas A Meyer,Michael Reth,Martin Ebeling,Per-Ola Freskgard,Jens Niewoehner,Sonja Schlicht,Peter Bruenker,Thomas Singer,Daniel Breustedt,Antonio Iglesias

doi:10.1007/s11095-018-2448-8

Felix Weber, Claas A Meyer + Show 9 more

Open Access

https://doi.org/10.1007/s11095-018-2448-8

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Abstract

PurposeAdministration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study aimed to investigate the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients.MethodsMice humanized for Fc gamma receptors (FcγRs) were generated by recombination-mediated genomic replacement. Body temperature, cytokine release and reactive oxygen species (ROS) were measured to assess FIR to mAbs.ResultsInfusion of human mAb specific for mouse transferrin receptor (HamTfR) into FcγR-humanized mice, produced marked transient hypothermia accompanied by an increase in inflammatory cytokines KC and MIP-2, and ROS. FIR were dependent on administration route and Fc-triggered effector functions mediated by neutrophils. Human neutrophils also induced FIR in wild type mice infused with HamTfR. Specific knock-in mice demonstrated that human FcγRIIIb on neutrophils was both necessary and sufficient to cause FIR. FcγRIIIb-mediated FIR was abolished by depleting neutrophils or blocking FcγRIIIb with CD11b antibodies.ConclusionsHuman FcγRIIIb and neutrophils are primarily responsible for triggering FIR. Clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcγRIIIb with specific mAbs.

Highlights

Monoclonal antibodies constitute an impressively effective class of biological drugs in the treatment of a number of severe conditions, including cancer, immune disorders and infections [1]
FcγRIIIb-mediated first infusion reactions (FIR) was abolished by depleting neutrophils or blocking FcγRIIIb with CD11b antibodies
Human FcγRIIIb and neutrophils are primarily responsible for triggering FIR

Summary

Introduction

Monoclonal antibodies (mAbs) constitute an impressively effective class of biological drugs in the treatment of a number of severe conditions, including cancer, immune disorders and infections [1]. While most infusion reactions are mild to moderate (e.g., skin rash, nausea, chill), in some patients these can be severe or life-threatening, e.g., anaphylactoid reactions or cytokine storm [2,3,4]. Infusion reactions are normally a primary phenomenon, known as first infusion reactions (FIR), and in most cases their incidence decreases significantly in subsequent infusions. Secondary infusion reactions (SIR) can result from accumulating anti-drug antibodies (ADAs) causing anaphylactoid reactions following repeated administrations of mAbs. SIRs resemble acute systemic anaphylaxis as mediated by immunoglobulin G (IgG) and are triggered mainly by neutrophils, but can be induced by monocyte/macrophages in mice [8]. Given the strong negative impact of FIR on the successful development of therapeutic mAbs, understanding the underlying mechanisms is of uppermost importance

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