| Autor: |
Kelly M. Loyet, Neil N. Trivedi, Racquel Corpuz, Brian L. Yaspan, Tracy Staton, Henry R. Maun, Erin H. Christensen, Kathila R. Alatsis, Xiumin Wu, Michael T. Lipari, Yvonne Franke, Mark S. Dennis, Daniel Kirchhofer, Wyne P. Lee, Rahul Ahuja, Xiaocheng Chen, Ashley Morando, Diana Chang, James T. Koerber, Aija Kusi, Joseph R. Arron, John Liu, Guiquan Jia, Juan Zhang, Janet Jackman, Ping Wu, George H. Caughey, Yan Wu, Rajesh Vij, Luz D. Orozco, Lawrence B. Schwartz, Benjamin T. Walters, Charles Eigenbrot, Prescott G. Woodruff, Lawren C. Wu, David F. Choy, Robert A. Lazarus, Meire Bremer, Amy Dressen, Magda Babina, Tangsheng Yi, Savita Ubhayakar, Xiaorong Liang, Jeff Lutman, Siddharth Sukumaran, Jason A. Hackney, John V. Fahy, Julie Q. Hang, Cary D. Austin, Manda Wong |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Cell, vol 179, iss 2
Cell |
| Popis: |
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 A 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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