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- Tobias Koschubs
- Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität (LMU) München, Feodor-Lynen-Str. 25, 81377 Munich, Germany
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- Stefan Dengl
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Harald Dürr
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Klaus Kaluza
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Guy Georges
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Christiane Hartl
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Stefan Jennewein
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Martin Lanzendörfer
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Johannes Auer
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Alvin Stern
- Roche, 340 Kingsland Street, Nutley, NJ 07110, U.S.A.
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- Kuo-Sen Huang
- Roche, 340 Kingsland Street, Nutley, NJ 07110, U.S.A.
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- Kathryn Packman
- Roche, 340 Kingsland Street, Nutley, NJ 07110, U.S.A.
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- Ueli Gubler
- Roche, 340 Kingsland Street, Nutley, NJ 07110, U.S.A.
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- Dirk Kostrewa
- Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität (LMU) München, Feodor-Lynen-Str. 25, 81377 Munich, Germany
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- Stefan Ries
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Silke Hansen
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Ulrich Kohnert
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
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- Patrick Cramer
- Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität (LMU) München, Feodor-Lynen-Str. 25, 81377 Munich, Germany
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- Olaf Mundigl
- Roche Diagnostics GmbH, Roche Biologics Research, Nonnenwald 2, 82377 Penzberg, Germany
説明
<jats:p>Hepsin is a type II transmembrane serine protease that is expressed in several human tissues. Overexpression of hepsin has been found to correlate with tumour progression and metastasis, which is so far best studied for prostate cancer, where more than 90% of such tumours show this characteristic. To enable improved future patient treatment, we have developed a monoclonal humanized antibody that selectively inhibits human hepsin and does not inhibit other related proteases. We found that our antibody, hH35, potently inhibits hepsin enzymatic activity at nanomolar concentrations. Kinetic characterization revealed non-linear, slow, tight-binding inhibition. This correlates with the crystal structure we obtained for the human hepsin–hH35 antibody Fab fragment complex, which showed that the antibody binds hepsin around α3-helix, located far from the active centre. The unique allosteric mode of inhibition of hH35 is distinct from the recently described HGFA (hepatocyte growth factor activator) allosteric antibody inhibition. We further explain how a small change in the antibody design induces dramatic structural rearrangements in the hepsin antigen upon binding, leading to complete enzyme inactivation.</jats:p>
収録刊行物
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- Biochemical Journal
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Biochemical Journal 442 (3), 483-494, 2012-02-24
Portland Press Ltd.