Details

Autor(en) / Beteiligte

• 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.
• Yi, Tangsheng

Titel

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

Ist Teil von

• Cell, 2019-10, Vol.179 (2), p.417-431.e19

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Increased tryptase levels in asthma that is independent of type 2 inflammation•Higher active allele β-tryptase count associated with lesser omalizumab response•Discovery, biochemistry, and structure of a noncompetitive inhibitory anti-tryptase•Favorable PK and potent inhibition of tryptase activity in mouse and primate models Type 2-low asthma represents a critical unmet need and an opportunity for new drug discovery. Here, Maun et al. demonstrate that increased mast cell tryptase levels are associated with asthma severity independent of type 2 inflammation and that increased active tryptase alleles are associated with decreased clinical responses to anti-IgE treatment. They generated a noncompetitive inhibitory anti-tryptase antibody with in vivo activity in humanized mouse and cynomolgus monkey models as a clinical candidate for severe asthma treatment.