An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Cell. 2019 Oct 3;179(2):417-431.e19. doi: 10.1016/j.cell.2019.09.009.

Abstract

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 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 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.

Keywords: allosteric protease inhibitor; anti-IgE; anti-tryptase; antibody engineering; asthma; mast cell; non-type 2 asthma; serine protease; tryptase; tryptase genetics.

MeSH terms

  • Adolescent
  • Allosteric Regulation / immunology
  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Asthma / therapy*
  • Cell Line
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mast Cells / enzymology*
  • Mast Cells / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Rabbits
  • Tryptases / antagonists & inhibitors*
  • Tryptases / immunology*

Substances

  • Antibodies, Monoclonal, Humanized
  • Tryptases