MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency

作者：Davtyan Hayk; Zagorski Karen; Petrushina Irina; Kazarian Konstantin; Goldberg Natalie R S; Petrosyan Janet; Blurton Jones Mathew; Masliah Eliezer; Cribbs David H; Agadjanyan Michael G^*; Ghochikyan Anahit^*

来源：Neurobiology of Aging, 2017, 59(7): 156-170.

DOI：10.1016/j.neurobiolaging.2017.08.006

• DNA vaccines
• MultiTEP platform
• Anti-alpha-synuclein antibodies
• B-cell mapping
• T-cell mapping
• Immunogenicity
• Therapeutic potency

We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa] 85-99, aa109-126, and aa126-140) of human alpha-synuclein (h alpha-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti-h alpha-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-h alpha-Syn T-helper cells. Generated antibodies recognize misfolded h alpha-Syn produced by neuroblastoma cells, h alpha-Syn in the brain tissues of transgenic mouse strains and in the brain tissues of dementia with Lewy body cases. Based on these results, the most promising vaccine targeting 3 B-cell epitopes of h alpha-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of h alpha-Syn with the aim to translate it to the human clinical trials.

• 出版日期2017-11