Abstract:
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.
