A immunotherapy has been a hot topic

Aβ immunotherapy has been a hot topic in recent years with the failure of several passive immunotherapies against Aβ. Many of these antibodies do not discriminate between the different Aβ sizes and conformations. Some prefer monomers but still react to larger glibenclamide while others have targeted the plaques but also react to smaller species. First, Solanezumab is an immunotherapy which, to date, uniquely targets monomers and oligomers but not fibrils. However, Solanezumab binds the monomer with higher affinity which means that the dose required to bind oligomers is much higher (Goure et al., 2014). Preferential binding of the monomer may explain why clinical trials failed to show improvement due to the fact that they used a lower dosage which may have been saturated by monomers (Goure et al., 2014; Doody et al., 2014). A similar reason was cited for the lack of efficacy of Bapineuzumab which binds monomer and oligomers with similar affinity but since oligomers are much less prevalent the dosage used may not have been adequate to see improvements (Goure et al., 2014). Bapineuzumab and most of the other immunotherapies tested recognize fibril Aβ as well as the smaller species. Additionally, antibodies that selectively recognize Aβ1–40 or Aβ1–42, Ponezumab and BiiB037 respectively, but do not discriminate between sizes did not prove to be effective (Goure et al., 2014). Ponezumab decreased plaque burden in 20month old Tg2576 mice indicating that it may act by disaggregating plaques which may not be beneficial (discussed later) (Carty et al., 2006). BiiB037 binds fibrils and oligomers with high affinity (Goure et al., 2014). These studies may indicate that specific targeting of one peptide, Aβ1–40 or Aβ1–42, may not be an effective target for immunotherapy or they may suffer from the same problem as other immunotherapies which are their lack of specificity for oligomeric Aβ1–40 or Aβ1–42. For a complete review on the targets of the major clinical trials see Goure et al. (2014). These trials and studies have shown that unspecific targeting or the targeting of plaques is not effective in the clinical setting. Solanezumab and Bapineuzumab indicate that targeting oligomers requires an antibody with lower affinity for the monomer, while Ponezumab and BiiB037 indicate that the size of the aggregate may be more important than the peptide isoform. This lack of specificity for the oligomer has stimulated research into more selective antibodies. With the lack of effective or safe immunotherapies, there has been a push to improve specificity with the idea that side effects can be minimized. Many researchers have managed to create monomer or fibril specific antibodies. Antibodies which target the N-terminal of Aβ can bind to fibrils and have been shown to increase the concentration of oligomers and thus increased toxicity through disaggregation (Liu et al., 2015b). Liu et al. (2015b) did not find the same increase in oligomer concentration when using C-terminal or mid-peptide recognizing antibodies. Another group tested a monomer specific antibody which was a precursor to Solanezumab. In J20 mice the Aβ concentration bound to the antibody in the blood increased but the oligomeric concentration in the cortex did not change nor did cognition improve (Mably et al., 2015). The study also tested a fibril antibody 1C22 which increased free Aβ in the blood but also did not influence cerebral oligomer levels or cognition (Mably et al., 2015). Additionally, 20% of the J20 mice immunized with either antibody died during the course of the study while control and PDAPP mice did not show the same mortality. These results indicate that extensive safety studies need to be pursued but Mably et al. (2015) did not look into the cause of death for these mice. These studies suggest that a specific oligomer antibody may be required to effectively improve cognition and decrease side effects. In 2014, a study was published which indicated the use of an oligomer specific conformation antibody eliminated synapse loss distant from plaques in Tg2576 mice and attenuated synapse loss in proximity to the plaques (Dorostkar et al., 2014). This group did not conduct behavior tests but it suggests that cognition could be improved with these antibodies. Additionally, Dorostkar et al. (2014) did not find significant changes with the IgG or pan-Aβ antibodies used. Oligomer specific antibodies need to be investigated more thoroughly to prove their efficacy and safety.