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 [4]. 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 [1],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) [2], 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 [3].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.


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