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Designing distribution of adjuvants: Synthesis of lipidated nucleic acid adjuvant compounds

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thesis
posted on 08.12.2021, 21:58 by Bilbrough, Timothy

Peptide vaccines can generate antigen-specific immune responses against tumours. However, peptides on their own are not usually immunogenic and require an adjuvant to ensure antigen-presenting cells are appropriately activated. Adjuvant localisation is essential for its activity; targeting an immunomodulatory compound to the lymph nodes appropriately positions it among a high density of immune cells, where immune responses are coordinated. Furthermore, systemic distribution of a potent immune modulator can lead to severe systemic toxicities. Lymph node targeting reduces systemic exposure with simultaneous reduction of side effects. Where a compound distributes in viva is determined by its pharmacokinetic properties and its route of administration. Once the route has been defined, a drug's pharmacokinetic properties can be modified by structural changes. To this end, we modified existing adjuvants to distribute into the lymphatics preferentially. One method was to increase the hydrophilicity and size of agalactosylceramide to favour lymphatic uptake. The second was to exploit albumin hitchhiking to access the lymph nodes. Here, a-galactosylceramide was chemically linked via an enzyme-labile linker to CpG ODN 1826, a TLR-9 agonist. The properties of each adjuvant mutually alter those of the other: to the CpG, a-galactosylceramide acts as an albumin binding domain; to the a-galactosylceramide, the CpG serves as a large hydrophilic group creating an amphiphile. In vivo, this should activate a strong, multilineage T cell response through the synergy of the two adjuvants. Furthermore, this should reduce the toxicity and side effects of the adjuvant by limiting its systemic distribution. This adjuvant may find further use in vaccines for diseases requiring a Thl response for effective clearance.

History

Copyright Date

01/01/2017

Date of Award

01/01/2017

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Drug Discovery and Development

Victoria University of Wellington Unit

Ferrier Research Institute

ANZSRC Type Of Activity code

1 Pure Basic Research

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Painter, Gavin; Anderson, Regan