First Infusion Reactions are Mediated by FcgammaRIIIb and Neutrophils.

Article Details

Citation

Weber F, Breustedt D, Schlicht S, Meyer CA, Niewoehner J, Ebeling M, Freskgard PO, Bruenker P, Singer T, Reth M, Iglesias A

First Infusion Reactions are Mediated by FcgammaRIIIb and Neutrophils.

Pharm Res. 2018 Jun 27;35(9):169. doi: 10.1007/s11095-018-2448-8.

PubMed ID
29951887 [ View in PubMed
]
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 (FcgammaRs) 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 FcgammaR-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 FcgammaRIIIb on neutrophils was both necessary and sufficient to cause FIR. FcgammaRIIIb-mediated FIR was abolished by depleting neutrophils or blocking FcgammaRIIIb with CD11b antibodies. CONCLUSIONS: Human FcgammaRIIIb 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 FcgammaRIIIb with specific mAbs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
NatalizumabLow affinity immunoglobulin gamma Fc region receptor III-BProteinHumans
Unknown
Ligand
Details