Dataset Information

First Infusion Reactions are Mediated by Fc?RIIIb and Neutrophils.

ABSTRACT:

Purpose

Administration 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.

Methods

Mice humanized for Fc gamma receptors (Fc?Rs) were generated by recombination-mediated genomic replacement. Body temperature, cytokine release and reactive oxygen species (ROS) were measured to assess FIR to mAbs.

Results

Infusion of human mAb specific for mouse transferrin receptor (HamTfR) into Fc?R-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 Fc?RIIIb on neutrophils was both necessary and sufficient to cause FIR. Fc?RIIIb-mediated FIR was abolished by depleting neutrophils or blocking Fc?RIIIb with CD11b antibodies.

Conclusions

Human Fc?RIIIb 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 Fc?RIIIb with specific mAbs.

SUBMITTER: Weber F

PROVIDER: S-EPMC6021477 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

First Infusion Reactions are Mediated by FcγRIIIb and Neutrophils.

Weber Felix F Breustedt Daniel D Schlicht Sonja S Meyer Claas A CA Niewoehner Jens J Ebeling Martin M Freskgard Per-Ola PO Bruenker Peter P Singer Thomas T Reth Michael M Iglesias Antonio A

Pharmaceutical research 20180627 9

<h4>Purpose</h4>Administration 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.<h4>Methods</h4>Mice humanized for Fc gamma receptors (FcγRs) were generated by recombination-mediated genomic replacement. Body temperature, cytokin ...[more]

PMID: 29951887

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