Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease*
- Michael Hanenberg‡,
- Jordan McAfoose‡,
- Luka Kulic‡,§,¶,
- Tobias Welt‡,
- Fabian Wirth‡,
- Petra Parizek‖,
- Lisa Strobel‡,
- Susann Cattepoel‡,
- Claudia Späni‡,
- Rebecca Derungs‡,
- Marcel Maier**,
- Andreas Plückthun‖ and
- Roger M. Nitsch‡1
- From the ‡Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren,
- the §Department of Neurology, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 26, 8091 Zurich,
- the ¶Zurich Center for Integrative Human Physiology and
- ‖Institute of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, and
- the **Neurimmune Holding AG, Wagistrasse 13, 8952 Schlieren, Switzerland
- ↵1 To whom correspondence should be addressed: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. Tel.: 41-44-634-88-71; Fax: 41-44-634-88-79; E-mail: nitsch{at}bli.uzh.ch.
Abstract
Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstrate the therapeutic potential of Aβ-specific DARPins for the treatment of Alzheimer disease.
Footnotes
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↵* This work was supported in part by the Swiss National Science Foundation and a Forschungskredit grant of the University of Zurich. S. Cattepoel is now an employee of CSL Behring AG, but declares no competing interests. M. Maier is now an employee of Neurimmune Holding AG, but declares no competing interests. A. Plückthun is a shareholder of Molecular Partners, commercializing the DARPin technology.
- Received March 26, 2014.
- Revision received July 19, 2014.
- © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
