PMID- 31913280
OWN - NLM
STAT- MEDLINE
DCOM- 20200413
LR  - 20210110
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 11
IP  - 1
DP  - 2020 Jan 8
TI  - The mechanistic and functional profile of the therapeutic anti-IgE antibody 
      ligelizumab differs from omalizumab.
PG  - 165
LID - 10.1038/s41467-019-13815-w [doi]
LID - 165
AB  - Targeting of immunoglobulin E (IgE) represents an interesting approach for the 
      treatment of allergic disorders. A high-affinity monoclonal anti-IgE antibody, 
      ligelizumab, has recently been developed to overcome some of the limitations 
      associated with the clinical use of the therapeutic anti-IgE antibody, 
      omalizumab. Here, we determine the molecular binding profile and functional 
      modes-of-action of ligelizumab. We solve the crystal structure of ligelizumab 
      bound to IgE, and report epitope differences between ligelizumab and omalizumab 
      that contribute to their qualitatively distinct IgE-receptor inhibition profiles. 
      While ligelizumab shows superior inhibition of IgE binding to FcepsilonRI, basophil 
      activation, IgE production by B cells and passive systemic anaphylaxis in an in 
      vivo mouse model, ligelizumab is less potent in inhibiting IgE:CD23 interactions 
      than omalizumab. Our data thus provide a structural and mechanistic foundation 
      for understanding the efficient suppression of FcepsilonRI-dependent allergic reactions 
      by ligelizumab in vitro as well as in vivo.
FAU - Gasser, Pascal
AU  - Gasser P
AUID- ORCID: 0000-0003-3708-1660
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland.
AD  - Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, 
      Switzerland.
FAU - Tarchevskaya, Svetlana S
AU  - Tarchevskaya SS
AD  - Department of Structural Biology, Stanford University School of Medicine, 
      Stanford, CA, 94305, USA.
FAU - Guntern, Pascal
AU  - Guntern P
AUID- ORCID: 0000-0001-8840-8577
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland.
AD  - Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, 
      Switzerland.
FAU - Brigger, Daniel
AU  - Brigger D
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland.
FAU - Ruppli, Rahel
AU  - Ruppli R
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland.
FAU - Zbaren, Noemi
AU  - Zbaren N
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland.
FAU - Kleinboelting, Silke
AU  - Kleinboelting S
AD  - Department of Structural Biology, Stanford University School of Medicine, 
      Stanford, CA, 94305, USA.
FAU - Heusser, Christoph
AU  - Heusser C
AD  - Pharmaceutical Research, Novartis AG, 4002, Basel, Switzerland.
FAU - Jardetzky, Theodore S
AU  - Jardetzky TS
AUID- ORCID: 0000-0002-3664-0072
AD  - Department of Structural Biology, Stanford University School of Medicine, 
      Stanford, CA, 94305, USA. tjardetzky@stanford.edu.
FAU - Eggel, Alexander
AU  - Eggel A
AUID- ORCID: 0000-0001-8746-3339
AD  - Department of BioMedical Research, University of Bern, Bern, Switzerland. 
      alexander.eggel@dbmr.unibe.ch.
AD  - Department of Rheumatology, Immunology and Allergology, University Hospital Bern, 
      Bern, Switzerland. alexander.eggel@dbmr.unibe.ch.
LA  - eng
GR  - R01 AI115469/AI/NIAID NIH HHS/United States
GR  - R01 HL141493/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200108
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Anti-Allergic Agents)
RN  - 0 (Antibodies, Anti-Idiotypic)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Receptors, IgE)
RN  - 0 (anti-IgE antibodies)
RN  - 2P471X1Z11 (Omalizumab)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - L8LE0L691T (ligelizumab)
SB  - IM
MH  - Animals
MH  - Anti-Allergic Agents/*administration & dosage/chemistry
MH  - Antibodies, Anti-Idiotypic/*administration & dosage/chemistry
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage
MH  - B-Lymphocytes/drug effects/immunology
MH  - Basophils/drug effects/immunology
MH  - Humans
MH  - Hypersensitivity/*drug therapy/immunology
MH  - Immunoglobulin E/chemistry/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Omalizumab/*administration & dosage/chemistry
MH  - Receptors, IgE/immunology
PMC - PMC6949303
COIS- C.H. and A.E. are consulting for Novartis Pharma AG. All other authors declare no 
      competing interests.
EDAT- 2020/01/09 06:00
MHDA- 2020/04/14 06:00
PMCR- 2020/01/08
CRDT- 2020/01/09 06:00
PHST- 2019/05/14 00:00 [received]
PHST- 2019/11/30 00:00 [accepted]
PHST- 2020/01/09 06:00 [entrez]
PHST- 2020/01/09 06:00 [pubmed]
PHST- 2020/04/14 06:00 [medline]
PHST- 2020/01/08 00:00 [pmc-release]
AID - 10.1038/s41467-019-13815-w [pii]
AID - 13815 [pii]
AID - 10.1038/s41467-019-13815-w [doi]
PST - epublish
SO  - Nat Commun. 2020 Jan 8;11(1):165. doi: 10.1038/s41467-019-13815-w.