Bidirectional Regulation of A beta Aggregates: Immunotherapy
Immunotherapy: Open Access has published an article entitled “Bidirectional Regulation of A beta Aggregates: Focus on TherapeuticTargets for Alzheimer's Disease” in its volume 3 Issue 3 written by Ying Zhang, and Jiang-Tao Li.
The article explains about Bidirectional Regulation of A beta Aggregates: Focus on TherapeuticTargets for Alzheimer's Disease.
Commentary was as follows regarding Alzheimer disease (AD) is the most prevalent dementia of agingadult, characterized by progressive amyloid aggregates in the brain andimpairment in cognition and memory. In recent year, data fromclinical trials and mouse models showed that Aβ immunotherapy hadbrought new hopes to AD treatment, although undesirable side effectsoccurred during the course of clinical trials based on Aβ targetingantibody drugs. Our previous study showed that single chain fragmentvariable (scFv) played key roles in ultrastructural regulation of Aβfibrillogenesis and disaggregation. In this invited commentary,bidirectional regulation of Aβ aggregates would be discussed as one ofthe methods for further study in AD treatment.
In our previous study, we developed single chain variable fragmentsagainst Abeta and evaluated their effects on the fibrillogenesis anddisaggregation of Abeta. We found that the scFv produced inbaculovirus and E. coli expression systems have a similar effect, whichnot only inhibit the Abeta fibril elongation but also disassemble themature Abeta fibrilin vitro. The scFvs showed an encouraging effectinvitro. This is an interesting study with a broader interest for researchersof not only Alzheimer’s disease, but also of other neurodegenerativediseases. In the past decade, scFv-based immunotherapies have beenreported to target various forms of protein aggregates including Aβ,SNCA, Htt, and PrP proteins . A novel 2N tau isoform-specific scFvhave been identified for experiment in a tau transgenic mouse model[5,6].Taken together, scFv-based in vitro regulation of Aβ aggregatesprovided valuable insight into the ultrastructural changes of Aβ aggregation and the prevention and therapeutic strategies for Aβtargeting immunotherapy in AD.
The blood-brain barrier (BBB) limits brain uptake of antibodies ,which will reduce the drug effect to some extent. The scFvs are usuallyproduced by fusing the variable regions of the antibody heavy (VH)and light chains (VL), creating a much smaller protein with unalteredspecificity to antigens. Because of its small size, scFvs are much easierto be delivered into the brain. The formula weight of the scFv is aboutonly one fifth of Immunoglobulin G (IgG) , which would apply togo through the BBB. Therefore, the advantage of elevatedconcentrations of scFv in the brain may increase the inhibition of Aβaggregation. Thefirst anti-Aβ scFv was produced by Frenkel et al.based on the variable regions of an anti-Aβ IgM 508 antibody .Single chain antibodies can be used to avoid antibody-dependentcell-mediated cytotoxicity (ADCC) and increase the safety of ADimmunotherapy. VH and VL domains form the antigen bindingregion, and the Fc fragment is not necessary for Aβ immunotherapy.Therefore, the size of entire drug molecules decrease and the sideeffects induced by Fc fragment should be avoided if the VH and VL areenough to control Aβ aggregates.Next step, alternative engineered antibodies can be developed onthe basis of single chain antibodies. The side effects of Aβimmunotherapy, such as meningoencephalitis, vasogenic edema orcerebral microhemorrhages, might also be avoided by novel forms ofantibodies including Fc-engineered antibodies, single domainantibodies, intrabodies, and bispecific antibodies.
Immunotherapy: Open Access
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