Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity

Aldehyde-containing triterpene saponins have adjuvant properties, but only those from Quillaja saponaria Molina stimulate the production of cytotoxic T lymphocytes (CTL) against exogenous antigens. Quillaja saponins have two normonoterpene ester moieties, linked linearly to their fucosyl residue, that play a critical role in the stimulation of CTL. These ester moieties are also responsible for these saponins' instability and toxicity. Based on the structure-activity relationships for the different groups of Q. saponaria saponins, new semi-synthetic analogs were developed that have the adjuvanticity of quillaja saponins, yet with less toxicity and greater stability in aqueous solutions. The quillaja saponin analogs were prepared by replacing their hydrolytically unstable ester groups with another lipophilic chain linked by a stable amide bond on these saponins' glucuronic acid residue. One of these analogs, GPI-0100, is a dodecylamide saponin derivative that stimulates an antibody isotype profile that corresponds to a Th1 type immune response, as well as CTL production against exogenous antigens.