6o1f

Publication Abstract from PubMed

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 A 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.

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.,Maun HR, Jackman JK, Choy DF, Loyet KM, Staton TL, Jia G, Dressen A, Hackney JA, Bremer M, Walters BT, Vij R, Chen X, Trivedi NN, Morando A, Lipari MT, Franke Y, Wu X, Zhang J, Liu J, Wu P, Chang D, Orozco LD, Christensen E, Wong M, Corpuz R, Hang JQ, Lutman J, Sukumaran S, Wu Y, Ubhayakar S, Liang X, Schwartz LB, Babina M, Woodruff PG, Fahy JV, Ahuja R, Caughey GH, Kusi A, Dennis MS, Eigenbrot C, Kirchhofer D, Austin CD, Wu LC, Koerber JT, Lee WP, Yaspan BL, Alatsis KR, Arron JR, Lazarus RA, Yi T Cell. 2019 Oct 3;179(2):417-431.e19. doi: 10.1016/j.cell.2019.09.009. PMID:31585081^[1]

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