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

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 correla... Full description

Journal Title: Cell October 3, 2019, Vol.179(2), pp.417-431.e19
Main Author: Maun, Henry R
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1097-4172 ; DOI: 10.1016/j.cell.2019.09.009
Link: http://search.proquest.com/docview/2301443681/?pq-origsite=primo
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title: An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.
format: Article
creator:
  • 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
subjects:
  • Allosteric Protease Inhibitor
  • Anti-Ige
  • Anti-Tryptase
  • Antibody Engineering
  • Asthma
  • Mast Cell
  • Non-Type 2 Asthma
  • Serine Protease
  • Tryptase
  • Tryptase Genetics
ispartof: Cell, October 3, 2019, Vol.179(2), pp.417-431.e19
description: 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,... •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.
language: eng
source:
identifier: E-ISSN: 1097-4172 ; DOI: 10.1016/j.cell.2019.09.009
fulltext: no_fulltext
issn:
  • 10974172
  • 1097-4172
url: Link


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titleAn Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.
creatorMaun, 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
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ispartofCell, October 3, 2019, Vol.179(2), pp.417-431.e19
identifierE-ISSN: 1097-4172 ; DOI: 10.1016/j.cell.2019.09.009
subjectAllosteric Protease Inhibitor ; Anti-Ige ; Anti-Tryptase ; Antibody Engineering ; Asthma ; Mast Cell ; Non-Type 2 Asthma ; Serine Protease ; Tryptase ; Tryptase Genetics
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descriptionSevere 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,... •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.
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titleAn Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.
authorMaun, 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
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atitleAn Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.
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issn00928674
date2019-10-03