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

Cell (2019-10-05)
Henry R Maun, Janet K Jackman, David F Choy, Kelly M Loyet, Tracy L Staton, Guiquan Jia, Amy Dressen, Jason A Hackney, Meire Bremer, Benjamin T Walters, Rajesh Vij, Xiaocheng Chen, Neil N Trivedi, Ashley Morando, Michael T Lipari, Yvonne Franke, Xiumin Wu, Juan Zhang, John Liu, Ping Wu, Diana Chang, Luz D Orozco, Erin Christensen, Manda Wong, Racquel Corpuz, Julie Q Hang, Jeff Lutman, Siddharth Sukumaran, Yan Wu, Savita Ubhayakar, Xiaorong Liang, Lawrence B Schwartz, Magda Babina, Prescott G Woodruff, John V Fahy, Rahul Ahuja, George H Caughey, Aija Kusi, Mark S Dennis, Charles Eigenbrot, Daniel Kirchhofer, Cary D Austin, Lawren C Wu, James T Koerber, Wyne P Lee, Brian L Yaspan, Kathila R Alatsis, Joseph R Arron, Robert A Lazarus, Tangsheng Yi

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.

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Triton X-100, laboratory grade
Guanidine hydrochloride, BioUltra, for molecular biology, ≥99.5% (AT)
N-Methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide, elastase substrate
L-Aspartic acid β-hydroxamate, serine racemase inhibitor

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