Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody reveals a potential role in airway diseases

Daniel J. Sexton, Ting Chen, Diana Martik, Petr Kuzmic, Guannan Kuang, Jie Chen, Andrew E. Nixon, Bruce L. Zuraw, Rosanna M. Forteza, William M. Abraham, Clive R. Wood

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

KLK1 (tissue kallikrein 1) is a member of the tissue kallikrein family of serine proteases and is the primary kinin-generating enzyme in human airways. DX-2300 is a fully human antibody that inhibits KLK1 via a competitive inhibition mechanism (Ki=0.13 nM). No binding of DX-2300 to KLK1 was observed in a surface-plasmon-resonance biosensor assay when KLK1 was complexed to known active-site inhibitors, suggesting that DX-2300 recognizes the KLK1 active site. DX-2300 did not inhibit any of the 21 serine proteases that were each tested at a concentration of 1 μM. We validated the use of DX-2300 for specific KLK1 inhibition by measuring the inhibition of KLK1-like activity in human urine, saliva and bronchoalveolar lavage fluid, which are known to contain active KLK1. In human tracheobronchial epithelial cells grown at the air/liquid interface, DX-2300 blocked oxidative-stress-induced epidermal-growth-factor receptor activation and downstream mucus cell proliferation and hypersecretion, which have been previously shown to be mediated by KLK1. In an allergic sheep model of asthma, DX-2300 inhibited both allergen-induced late-phase bronchoconstriction and airway hyper-responsiveness to carbachol. These studies demonstrate that DX-2300 is a potent and specific inhibitor of KLK1 that is efficacious in in vitro and in vivo models of airway disease.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalBiochemical Journal
Volume422
Issue number2
DOIs
StatePublished - Sep 1 2009

Keywords

  • Antibody inhibition of protease
  • Asthma
  • Bradykinin
  • Chronic obstructive pulmonary disease
  • Kallikrein
  • Kinin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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    Sexton, D. J., Chen, T., Martik, D., Kuzmic, P., Kuang, G., Chen, J., Nixon, A. E., Zuraw, B. L., Forteza, R. M., Abraham, W. M., & Wood, C. R. (2009). Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody reveals a potential role in airway diseases. Biochemical Journal, 422(2), 383-392. https://doi.org/10.1042/BJ20090010