PMID- 29951887
OWN - NLM
STAT- MEDLINE
DCOM- 20190624
LR  - 20190624
IS  - 1573-904X (Electronic)
IS  - 0724-8741 (Print)
IS  - 0724-8741 (Linking)
VI  - 35
IP  - 9
DP  - 2018 Jun 27
TI  - First Infusion Reactions are Mediated by FcgammaRIIIb and Neutrophils.
PG  - 169
LID - 10.1007/s11095-018-2448-8 [doi]
LID - 169
AB  - 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.
FAU - Weber, Felix
AU  - Weber F
AD  - Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, 
      Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Bldg 93 Room 5.10, 
      Grenzacherstrasse 124, 4070, Basel, CH, Switzerland.
FAU - Breustedt, Daniel
AU  - Breustedt D
AD  - Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, 
      Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Bldg 93 Room 5.10, 
      Grenzacherstrasse 124, 4070, Basel, CH, Switzerland.
AD  - Novartis Pharma AG, Novartis Institutes for Biomedical Research, Basel, 
      Switzerland.
FAU - Schlicht, Sonja
AU  - Schlicht S
AD  - Small Molecule Research, Therapeutic Modalities, Roche Innovation Center Basel, 
      Basel, Switzerland.
FAU - Meyer, Claas A
AU  - Meyer CA
AD  - Small Molecule Research, Therapeutic Modalities, Roche Innovation Center Basel, 
      Basel, Switzerland.
FAU - Niewoehner, Jens
AU  - Niewoehner J
AD  - Large Molecule Research, Therapeutic Modalities, Roche Innovation Center Munich, 
      Munich, Germany.
FAU - Ebeling, Martin
AU  - Ebeling M
AD  - Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, 
      Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Bldg 93 Room 5.10, 
      Grenzacherstrasse 124, 4070, Basel, CH, Switzerland.
FAU - Freskgard, Per-Ola
AU  - Freskgard PO
AD  - Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, 
      Roche Innovation Center Basel, Basel, Switzerland.
FAU - Bruenker, Peter
AU  - Bruenker P
AD  - Large Molecule Research, Roche Innovation Center Zurich, Schlieren, Switzerland.
FAU - Singer, Thomas
AU  - Singer T
AD  - Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, 
      Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Bldg 93 Room 5.10, 
      Grenzacherstrasse 124, 4070, Basel, CH, Switzerland.
FAU - Reth, Michael
AU  - Reth M
AD  - Institute of Biology III (Molecular Immunology), University of Freiburg, Freiburg 
      im Breisgau, Germany.
FAU - Iglesias, Antonio
AU  - Iglesias A
AD  - Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, 
      Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Bldg 93 Room 5.10, 
      Grenzacherstrasse 124, 4070, Basel, CH, Switzerland. antonio.iglesias@roche.com.
LA  - eng
PT  - Journal Article
DEP - 20180627
PL  - United States
TA  - Pharm Res
JT  - Pharmaceutical research
JID - 8406521
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (FCGR3B protein, human)
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (Receptors, IgG)
RN  - 0 (Receptors, Transferrin)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage/*adverse effects/immunology
MH  - GPI-Linked Proteins/genetics/immunology
MH  - Humans
MH  - Hypothermia/*chemically induced/immunology
MH  - Inflammation/*chemically induced/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neutrophils/drug effects/*immunology
MH  - Receptors, IgG/genetics/*immunology
MH  - Receptors, Transferrin/immunology
PMC - PMC6021477
OTO - NOTNLM
OT  - human FcgammaRIIIb
OT  - humanized mouse model
OT  - immunotoxicology
OT  - infusion reactions
OT  - neutrophils
EDAT- 2018/06/29 06:00
MHDA- 2019/06/25 06:00
PMCR- 2018/06/27
CRDT- 2018/06/29 06:00
PHST- 2018/03/29 00:00 [received]
PHST- 2018/06/15 00:00 [accepted]
PHST- 2018/06/29 06:00 [entrez]
PHST- 2018/06/29 06:00 [pubmed]
PHST- 2019/06/25 06:00 [medline]
PHST- 2018/06/27 00:00 [pmc-release]
AID - 10.1007/s11095-018-2448-8 [pii]
AID - 2448 [pii]
AID - 10.1007/s11095-018-2448-8 [doi]
PST - epublish
SO  - Pharm Res. 2018 Jun 27;35(9):169. doi: 10.1007/s11095-018-2448-8.