title: Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody reveals a potential role in airway diseases.
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 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.
authors.affiliation: Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, USA. dsexton@dyax.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sexton
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Diana
authors.initials: D
authors.lastname: Martik
authors.forename: Petr
authors.initials: P
authors.lastname: Kuzmic
authors.forename: Guannan
authors.initials: G
authors.lastname: Kuang
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Nixon
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Zuraw
authors.forename: Rosanna M
authors.initials: RM
authors.lastname: Forteza
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Clive R
authors.initials: CR
authors.lastname: Wood
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D001249:Asthma / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D012756:Sheep; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D020840:Tissue Kallikreins