Bivalent antibody pliers inhibit β-tryptase by an allosteric mechanism dependent on the IgG hinge

Henry R. Maun, Rajesh Vij, Benjamin T. Walters, Ashley Morando, Janet K. Jackman, Ping Wu, Alberto Estevez, Xiaocheng Chen, Yvonne Franke, Michael T. Lipari, Mark S. Dennis, Daniel Kirchhofer, Claudio Ciferri, Kelly M. Loyet, Tangsheng Yi, Charles Eigenbrot, Robert A. Lazarus () and James T. Koerber ()
Additional contact information
Henry R. Maun: Department of Early Discovery Biochemistry, Genentech, Inc.
Rajesh Vij: Genentech, Inc.
Benjamin T. Walters: Genentech, Inc.
Ashley Morando: Genentech, Inc.
Janet K. Jackman: Genentech, Inc.
Ping Wu: Genentech, Inc.
Alberto Estevez: Genentech, Inc.
Xiaocheng Chen: Genentech, Inc.
Yvonne Franke: Genentech, Inc.
Michael T. Lipari: Department of Early Discovery Biochemistry, Genentech, Inc.
Mark S. Dennis: Genentech, Inc.
Daniel Kirchhofer: Department of Early Discovery Biochemistry, Genentech, Inc.
Claudio Ciferri: Genentech, Inc.
Kelly M. Loyet: Genentech, Inc.
Tangsheng Yi: Genentech, Inc.
Charles Eigenbrot: Genentech, Inc.
Robert A. Lazarus: Department of Early Discovery Biochemistry, Genentech, Inc.
James T. Koerber: Genentech, Inc.

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of allergic inflammatory responses in asthma. Antibodies generally inhibit proteases by blocking substrate access by binding to active sites or exosites or by allosteric modulation. The bivalency of IgG antibodies can increase potency via avidity, but has never been described as essential for activity. Here we report an inhibitory anti-tryptase IgG antibody with a bivalency-driven mechanism of action. Using biochemical and structural data, we determine that four Fabs simultaneously occupy four exosites on the β-tryptase tetramer, inducing allosteric changes at the small interface. In the presence of heparin, the monovalent Fab shows essentially no inhibition, whereas the bivalent IgG fully inhibits β-tryptase activity in a hinge-dependent manner. Our results suggest a model where the bivalent IgG acts akin to molecular pliers, pulling the tetramer apart into inactive β-tryptase monomers, and may provide an alternative strategy for antibody engineering.

Date: 2020
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DOI: 10.1038/s41467-020-20143-x

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