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Immunological approaches to reduce cerebral Aß levels are explored intensively worldwide. Besides active Aß-immunization different forms of passive immunization are pursued.
Bapineuzumab (a monoclonal antibody recognizing the N-terminus of Aβ) is currently the best characterized immunotherapeutic with regard to its clinical- and biological activity. Bapineuzumab is the first AD immuntherapeutic entering phase III clinical testing. Currently two large, international, multicenter studies are conducted to validate its efficacy. As of early 2011, clinical development of Solanezumab (LY2062430), an Aß antibody developed by Eli Lilly, has caught up to bapineuzumab. After a short clinical phase II focusing on pharmacokinetic aspects, solanezumab has entered clinical phase III testing. Two further Aß antibodies, PF04360365 (Pfizer) and GSK933776A (GSK), are tested clinically.
Human Intravenous Immunoglobulin (IVIG) preparations contain antibodies of multiple specificities. In addition to those specific for Aβ, they were found to contain antibodies specific for other molecules potentially involved in AD pathogenesis such as RAGE and sLRP. Both are involved in the transport of Aβ: RAGE is involved in the transport of Aβ from plasma to the central nervous system; sLRP modulates Aβ efflux from the central nervous system to the plasma compartment. Two companies, Baxter and Octapharma, are testing their IVIG preparations in clinical trials in AD.
Alzheimer vaccines
Currently at least five Alzheimer vaccines are clinically investigated: ACC001 (Elan/Wyeth), CAD106 (Novartis/Cytos), V950 (Merck/Acumen) as well as the AFFITOPE® vaccines AD01, AD02 and AD03 which are developed by AFFiRiS together with GSKBio. These second generation AD vaccines are characterized by short, Aβ-representing antigens. They serve as target structure for the antibody response. The safety concept of short antigens is supposed to preclude the activation of Aβ-specific, potentially encephalitogenic T-cells. The said safety concept is implemented in all second generation vaccines and appears to be effective: Up to date no cases of meningoencephalitis have been reported for any of the second generation AD vaccines.
AFFiRiS is broadening the target spectrum towards the modified forms of Aβ with the vaccine candidate AD03. Recent research identified truncated and pyroglutamate-modified Aβ species to act as seed for Aβ aggregation and to be particularly toxic.
