1. An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma
- Author
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Maun, Henry R, Jackman, Janet K, Choy, David F, Loyet, Kelly M, Staton, Tracy L, Jia, Guiquan, Dressen, Amy, Hackney, Jason A, Bremer, Meire, Walters, Benjamin T, Vij, Rajesh, Chen, Xiaocheng, Trivedi, Neil N, Morando, Ashley, Lipari, Michael T, Franke, Yvonne, Wu, Xiumin, Zhang, Juan, Liu, John, Wu, Ping, Chang, Diana, Orozco, Luz D, Christensen, Erin, Wong, Manda, Corpuz, Racquel, Hang, Julie Q, Lutman, Jeff, Sukumaran, Siddharth, Wu, Yan, Ubhayakar, Savita, Liang, Xiaorong, Schwartz, Lawrence B, Babina, Magda, Woodruff, Prescott G, Fahy, John V, Ahuja, Rahul, Caughey, George H, Kusi, Aija, Dennis, Mark S, Eigenbrot, Charles, Kirchhofer, Daniel, Austin, Cary D, Wu, Lawren C, Koerber, James T, Lee, Wyne P, Yaspan, Brian L, Alatsis, Kathila R, Arron, Joseph R, Lazarus, Robert A, and Yi, Tangsheng
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Clinical Research ,Asthma ,Lung ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Respiratory ,Adolescent ,Allosteric Regulation ,Animals ,Antibodies ,Monoclonal ,Humanized ,Cell Line ,Female ,Humans ,Macaca fascicularis ,Male ,Mast Cells ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred NOD ,Mice ,SCID ,Rabbits ,Tryptases ,allosteric protease inhibitor ,anti-IgE ,anti-tryptase ,antibody engineering ,asthma ,mast cell ,non-type 2 asthma ,serine protease ,tryptase ,tryptase genetics ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2019