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

• Published in: Neurobiology of aging 2017-11, Vol.59, p.156-170
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - immunology; Animals; Anti-α-synuclein antibodies; Antibodies; B-cell mapping; DNA vaccines; Epitopes, B-Lymphocyte - immunology; Female; Humans; Immunogenicity; Mice, Inbred C57BL; Mice, Transgenic; MultiTEP platform; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - immunology; Neurodegenerative Diseases - therapy; T-cell mapping; T-Lymphocytes, Helper-Inducer - immunology; Therapeutic potency; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.08.006

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 (hα-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti-hα-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-hα-Syn T-helper cells. Generated antibodies recognize misfolded hα-Syn produced by neuroblastoma cells, hα-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 hα-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of hα-Syn with the aim to translate it to the human clinical trials.