Engineered antibody approaches for Alzheimer's disease immunotherapy

The accumulation of amyloid-β-peptide (Aβ or A-beta) in the brain is considered to be a key event in the pathogenesis of Alzheimer's disease (AD). Over the last decade, antibody strategies aimed at reducing high levels of Aβ in the brain and or neutralizing its toxic effects have emerged as one of the most promising treatments for AD. Early approaches using conventional antibody formats demonstrated the potential of immunotherapy, but also caused a range of undesirable side effects such meningoencephalitis, vasogenic edema or cerebral microhemorrhages in both murine and humans. This prompted the exploration of alternative approaches using engineered antibodies to avoid adverse immunological responses and provide a safer and more effective therapy. Encouraging results have been obtained using a range of recombinant antibody formats including, single chain antibodies, antibody domains, intrabodies, bispecific antibodies as well as Fc-engineered antibodies in transgenic AD mouse and primate models. This review will address recent progress using these recombinant antibodies against Aβ, highlighting their advantages over conventional monoclonal antibodies and delivery methods.