title: Design and synthesis of potent Quillaja saponin vaccine adjuvants.
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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, and the Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Adams
authors.forename: Payal
authors.initials: P
authors.lastname: Damani
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Perl
authors.forename: Annie
authors.initials: A
authors.lastname: Won
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000302:isolation & purification; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D031990:Quillaja / Q000737:chemistry*; D012503:Saponins / Q000138:chemical synthesis* / Q000276:immunology* / Q000302:isolation & purification; D014612:Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D012503:Saponins; D014612:Vaccines