A{beta}-specific DARPins as a novel class of potential therapeutics for Alzheimer’s disease [Immunology]

September 4th, 2014 by Hanenberg, M., McAfoose, J., Kulic, L., Welt, T., Wirth, F., Parizek, P., Strobel, L., Cattepoel, S., Spani, C., Derungs, R., Maier, M., Pluckthun, A., Nitsch, R. M.

Passive immunization with anti-Aβ antibodies is effective in animal models of Alzheimer′s disease (AD). 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 3xD23) were infused intracerebroventricularly into brains of 11 months old Tg2576 mice over four weeks. Both D23 and 3xD23 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 AD.