PMID- 24401277
OWN - NLM
STAT- MEDLINE
DCOM- 20140407
LR  - 20211021
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 124
IP  - 2
DP  - 2014 Feb
TI  - Human IgG Fc domain engineering enhances antitoxin neutralizing antibody 
      activity.
PG  - 725-9
LID - 72676 [pii]
LID - 10.1172/JCI72676 [doi]
AB  - The effector activity of antibodies is dependent on engagement with Fcgamma receptors 
      (FcgammaRs) and activation of the associated intracellular signaling pathways. 
      Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the 
      interactions of their Fc regions with FcgammaRs is hampered by substantial structural 
      and functional FcgammaR diversity among species. In this report, we used mice 
      expressing only human FcgammaRs to evaluate the contribution of FcgammaR-mediated 
      pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We 
      observed that the protective activity of this mAb was highly dependent upon FcgammaR 
      engagement, with minimal protection against anthrax toxin observed in 
      FcgammaR-deficient mice following mAb administration. We generated anti-anthrax toxin 
      mAbs with specific Fc domain variants with selectively enhanced affinity for 
      particular human FcgammaRs and assessed their activity in FcgammaR-humanized mice. We 
      determined that Fc domain variants that were capable of selectively engaging 
      activating FcgammaRs substantially enhanced the in vitro and in vivo activity of 
      anthrax toxin-neutralizing antibodies. These findings indicate that the 
      application of Fc domain engineering is a feasible strategy to enhance 
      toxin-neutralizing activity and suggest that engineered antitoxin antibodies will 
      have improved therapeutic efficacy.
FAU - Bournazos, Stylianos
AU  - Bournazos S
FAU - Chow, Siu-Kei
AU  - Chow SK
FAU - Abboud, Nareen
AU  - Abboud N
FAU - Casadevall, Arturo
AU  - Casadevall A
FAU - Ravetch, Jeffrey V
AU  - Ravetch JV
LA  - eng
GR  - U54 AI057158/AI/NIAID NIH HHS/United States
GR  - 5U54AI057158/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140109
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Antitoxins)
RN  - 0 (Bacterial Toxins)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, IgG)
RN  - 0 (Recombinant Proteins)
RN  - 0 (anthrax toxin)
SB  - IM
MH  - Animals
MH  - Anthrax/therapy
MH  - Antibodies, Monoclonal/chemistry
MH  - Antibodies, Neutralizing/*chemistry
MH  - Antibody-Dependent Cell Cytotoxicity/immunology
MH  - Antigens, Bacterial/chemistry
MH  - Antitoxins/chemistry
MH  - Bacterial Toxins/chemistry
MH  - Enzyme-Linked Immunosorbent Assay
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoglobulin G/*chemistry
MH  - Inhibitory Concentration 50
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Engineering
MH  - Protein Structure, Tertiary
MH  - Receptors, IgG/*chemistry
MH  - Recombinant Proteins/chemistry
MH  - Signal Transduction
MH  - Surface Plasmon Resonance
PMC - PMC3904629
EDAT- 2014/01/10 06:00
MHDA- 2014/04/08 06:00
PMCR- 2014/01/09
CRDT- 2014/01/10 06:00
PHST- 2013/08/12 00:00 [received]
PHST- 2013/10/30 00:00 [accepted]
PHST- 2014/01/10 06:00 [entrez]
PHST- 2014/01/10 06:00 [pubmed]
PHST- 2014/04/08 06:00 [medline]
PHST- 2014/01/09 00:00 [pmc-release]
AID - 72676 [pii]
AID - 10.1172/JCI72676 [doi]
PST - ppublish
SO  - J Clin Invest. 2014 Feb;124(2):725-9. doi: 10.1172/JCI72676. Epub 2014 Jan 9.