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Structure paper

TitleDirected evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 7069, Year 2021
Publish dateDec 3, 2021
AuthorsLuke F Pennington / Pascal Gasser / Silke Kleinboelting / Chensong Zhang / Georgios Skiniotis / Alexander Eggel / Theodore S Jardetzky /
PubMed AbstractAntibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional ...Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated "disruption" of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells.
External linksNat Commun / PubMed:34862384 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.75 - 7.29 Å
Structure data

25136

7sht

EMDB-25136, PDB-7sht:
Structure of a partially disrupted IgE high affinity receptor complex bound to an omalizumab variant
Method: EM (single particle) / Resolution: 7.29 Å

PDB-7shu:
IgE-Fc in complex with omalizumab variant C02
Method: X-RAY DIFFRACTION / Resolution: 2.75 Å

PDB-7shy:
IgE-Fc in complex with omalizumab scFv
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

PDB-7shz:
IgE-Fc in complex with HAE
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

PDB-7si0:
IgE-Fc in complex with 813
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-PO4:
PHOSPHATE ION

ChemComp-HOH:
WATER

ChemComp-GOL:
GLYCEROL

ChemComp-MAN:
alpha-D-mannopyranose

ChemComp-ACT:
ACETATE ION

ChemComp-NA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / IgE / allergy / Xolair / Omalizumab / inhibitor / E27

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