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J. Biol. Chem., Vol. 282, Issue 4, 2229-2236, January 26, 2007

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A Role for Protein Misfolding in Immunogenicity of Biopharmaceuticals^*

Coen Maas, Suzanne Hermeling^¶, Barend Bouma, Wim Jiskoot¹, and Martijn F. B. G. Gebbink²

From the Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht and the Institute for Biomembranes, Padualaan 8, 3584 CH Utrecht, and the Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), P. O. Box 80082, 3508 TB Utrecht, and the ^¶Central Laboratory Animal Institute, Utrecht University, P. O. Box 80190, 3508 TD Utrecht, The Netherlands

For largely unknown reasons, biopharmaceuticals evoke potentially harmful antibody formation. Such antibodies can inhibit drug efficacy and, when directed against endogenous proteins, cause life-threatening complications. Insight into the mechanisms by which biopharmaceuticals break tolerance and induce an immune response will contribute to finding solutions to prevent this adverse effect. Using a transgenic mouse model, we here demonstrate that protein misfolding, detected with the use of tissue-type plasminogen activator and thioflavin T, markers of amyloid-like properties, results in breaking of tolerance. In wild-type mice, misfolding enhances protein immunogenicity. Several commercially available biopharmaceutical products were found to contain misfolded proteins. In some cases, the level of misfolded protein was found to increase upon storage under conditions prescribed by the manufacturer. Our results indicate that misfolding of therapeutic proteins is an immunogenic signal and a risk factor for immunogenicity. These findings offer novel possibilities to detect immunogenic protein entities with tPA and reduce immunogenicity of biopharmaceuticals.

Received for publication, June 22, 2006 , and in revised form, September 27, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Present address: Div. of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.

² To whom correspondence should be addressed: P. O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: 3130-2506513; Fax: 3130-2511893; E-mail: m.gebbink{at}umcutrecht.nl.

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