Design and Synthesis of Potent Quillaja Saponin Vaccine Adjuvants

Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of the American Chemical Society (Impact Factor: 11.44). 02/2010; 132(6):1939-45. DOI: 10.1021/ja9082842
Source: PubMed

ABSTRACT The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that significantly enhances the immune response to a coadministered antigen. Only a handful of adjuvants have both sufficient potency and acceptable toxicity for clinical investigation. One promising adjuvant is QS-21, a saponin natural product that is the immunopotentiator of choice in many cancer and infectious disease vaccine clinical trials. However, the therapeutic promise of QS-21 adjuvant is curtailed by several factors, including its scarcity, difficulty in purification to homogeneity, dose-limiting toxicity, and chemical instability. Here, we report the design, synthesis, and evaluation of chemically stable synthetic saponins. These novel, amide-modified, non-natural substances exhibit immunopotentiating effects in vivo that rival or exceed that of QS-21 in evaluations with the GD3-KLH melanoma conjugate vaccine. The highly convergent synthetic preparation of these novel saponins establishes new avenues for discovering improved molecular adjuvants for specifically tailored vaccine therapies.

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Available from: Payal Damani-Yokota, Mar 19, 2014
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    • "Saponins are secondary metabolites widely distributed in plants, characterized by the presence of a skeleton derived from a 30-carbon 2,3-oxidosqualene precursor, to which one or more sugar residues are linked [4] [5]. The complex structure and its higher variability are factors responsible for difficulties in isolating and synthesizing these molecules [6]. These obstacles, associated with the often low concentration of saponins in biomass, highlight the need for developing ways to increase their content in plants prior to extraction. "
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    • "The synthesis was analogous to that described in detail by Adams et al. (2010) and performed under an argon atmosphere . A solution of n-butyllithium in pentane (1.2 mL, 2.24 mmol, 3.3 equivalent) was added dropwise to a solution of diisopropylamine (300 lL, 2.24 mmol, 3.3 equivalent) in tetrahydrofuran (3 mL) cooled to –78 °C. "
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    • "It is worth noting that the mechanism by which saponin potentiates an immune response remains unclear. Hypotheses have been raised about whether saponin, through lectin-mediated cell membrane interactions, could facilitate the uptake of the antigen into antigen-presenting cells, leading to specific cytokine profiles that enhance T and/or B-cell responses (Kensil 1996, Marciani 2003, Adams et al. 2010). "
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