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.
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September 2009
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Research Article|
August 13 2009
Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody reveals a potential role in airway diseases
Daniel J. Sexton;
Daniel J. Sexton
1
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
1To whom correspondence should be sent (email dsexton@dyax.com).
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Ting Chen;
Ting Chen
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Diana Martik;
Diana Martik
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Petr Kuzmic;
Petr Kuzmic
†BioKin Ltd, 15 Main Street, Suite 232, Watertown, MA 02472, U.S.A.
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Guannan Kuang;
Guannan Kuang
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Jie Chen;
Jie Chen
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Andrew E. Nixon;
Andrew E. Nixon
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Bruce L. Zuraw;
Bruce L. Zuraw
‡Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, U.S.A.
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Rosanna M. Forteza;
Rosanna M. Forteza
§Division of Pulmonary and Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, U.S.A.
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William M. Abraham;
William M. Abraham
¶Department of Research, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, U.S.A.
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Clive R. Wood
Clive R. Wood
*Discovery Research, Dyax Corp., 300 Technology Square, Cambridge, MA 02139, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 06 2009
Revision Received:
June 09 2009
Accepted:
June 16 2009
Accepted Manuscript online:
June 16 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 422 (2): 383–392.
Article history
Received:
January 06 2009
Revision Received:
June 09 2009
Accepted:
June 16 2009
Accepted Manuscript online:
June 16 2009
Citation
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; Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody reveals a potential role in airway diseases. Biochem J 1 September 2009; 422 (2): 383–392. doi: https://doi.org/10.1042/BJ20090010
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