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Publication Abstract from PubMed

Human beta-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 beta-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 beta-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 beta-tryptase monomers, and may provide an alternative strategy for antibody engineering.

Bivalent antibody pliers inhibit beta-tryptase by an allosteric mechanism dependent on the IgG hinge.,Maun HR, Vij R, Walters BT, Morando A, Jackman JK, Wu P, Estevez A, Chen X, Franke Y, Lipari MT, Dennis MS, Kirchhofer D, Ciferri C, Loyet KM, Yi T, Eigenbrot C, Lazarus RA, Koerber JT Nat Commun. 2020 Dec 22;11(1):6435. doi: 10.1038/s41467-020-20143-x. PMID:33353951^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.