Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex.

Autor: Pennington LF; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Progam in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford, CA, 94305, USA., Gasser P; Department of Rheumatology and Immunology, University Hospital Bern, Bern, Switzerland.; Department of BioMedical Research, University of Bern, Bern, Switzerland., Kleinboelting S; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA., Zhang C; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA., Skiniotis G; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA., Eggel A; Department of Rheumatology and Immunology, University Hospital Bern, Bern, Switzerland.; Department of BioMedical Research, University of Bern, Bern, Switzerland., Jardetzky TS; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. tjardetz@stanford.edu.; Progam in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. tjardetz@stanford.edu.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford, CA, 94305, USA. tjardetz@stanford.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Dec 03; Vol. 12 (1), pp. 7069. Date of Electronic Publication: 2021 Dec 03.
DOI: 10.1038/s41467-021-27397-z
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
Externí odkaz: