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

Published online

Journal Article

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 microM. 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.

Full Text

Duke Authors

Cited Authors

  • Sexton, DJ; Chen, T; Martik, D; Kuzmic, P; Kuang, G; Chen, J; Nixon, AE; Zuraw, BL; Forteza, RM; Abraham, WM; Wood, CR

Published Date

  • August 13, 2009

Published In

Volume / Issue

  • 422 / 2

Start / End Page

  • 383 - 392

PubMed ID

  • 19527222

Pubmed Central ID

  • 19527222

Electronic International Standard Serial Number (EISSN)

  • 1470-8728

Digital Object Identifier (DOI)

  • 10.1042/BJ20090010

Language

  • eng

Conference Location

  • England