Preclinical evaluation of a vaccine against IL-17 mediated inflammatory diseases including psoriasis

Psoriasis is a chronic autoimmune skin condition. Interleukin 17A (IL-17A) is a pro-inflammatory cytokine with a key role in the pathogenesis of this disease. Antibodies targeting IL-17A have shown superior efficacy compared with other psoriasis treatments, and long-term studies have demonstrated these to be safe in humans. Nevertheless, despite the excellent safety and efficacy record of these monoclonal antibodies in psoriasis treatment, patient access to these new first line therapies is restricted for financial reasons. Replacing passive immunisation by therapeutic vaccination targeting IL-17A has the potential to overcome this serious impediment and address this currently unmet medical need. A series of experiments were performed in mice as proof of concept for the primary pharmacodynamic action of such a vaccine and in order to obtain informative data on the principle pharmacokinetic parameters. We used the most widely employed in vivo model for psoriasis, the topical imiquimod challenge. This elicits a psoriasis-like skin disease, which has been extensively characterised and, importantly, involves IL-17A signaling. A concern with auto-vaccines is safety. The data demonstrate that the vaccine-induced antibody titre is reversible, that it can be boosted by a variety of immunisation schedules, and that antibody titres are not affected by an imiquimod-induced psoriasis-like inflammatory flare. Furthermore, the antibody response generated was highly specific, as no significant antibodies reactive to the most closely related isoform, IL-17F, were detectable. Most importantly, we conducted a head-to-head comparison with a monoclonal antibody targeting IL-17A, which is known to be highly effective against psoriasis, to assess efficacy. The results show that in mice the vaccine effects are of equal efficacy to injected IL-17A monoclonal antibodies. These findings support the rationale for clinical development of the vaccine.

Name dc:type.qualificationname

Master of Science

Level dc:type.qualificationlevel

Master's Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2017

Author dc:creator

• West, Jonathan David

Advisors dc:contributor.advisor

• Foerster, John
• Berg, Jonathan

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/2308633d-0690-40f9-9635-593997239ad7

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/2308633d-0690-40f9-9635-593997239ad7