期刊
CELL
卷 179, 期 2, 页码 417-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.09.009
关键词
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资金
- NHLBI NIH HHS [P01 HL107202] Funding Source: Medline
- NIAID NIH HHS [U19 AI077439] Funding Source: Medline
Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active beta-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 beta-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 angstrom crystal structure of a beta-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization.This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis,and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics.These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.
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