An Allosteric Anti-Tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma
64 Pages Posted: 3 Mar 2019 Last revised: 29 May 2019 Sneak Peek Status: Review CompleteMore...
Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and have significant unmet medical needs. We show that mast cell tryptase is elevated in severe asthma patients, correlating with greater disease severity, but independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveals the molecular basis for allosteric destabilization of both small and large interfaces required for tetramerization. Anti-tryptase potently blocks tryptase-dependent activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and has favorable pharmacokinetics in cynomolgus monkeys. Our data provide the foundation for developing anti-tryptase as a clinical therapy for severe asthma.
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