title: Design, synthesis, and immunologic evaluation of vaccine adjuvant conjugates based on QS-21 and tucaresol.
abstract: Immunoadjuvants are used to potentiate the activity of modern subunit vaccines that are based on molecular antigens. An emerging approach involves the combination of multiple adjuvants in a single formulation to achieve optimal vaccine efficacy. Herein, to investigate such potential synergies, we synthesized novel adjuvant conjugates based on the saponin natural product QS-21 and the aldehyde tucaresol via chemoselective acylation of an amine at the terminus of the acyl chain domain in QS saponin variants. In a preclinical mouse vaccination model, these QS saponin-tucaresol conjugates induced antibody responses similar to or slightly higher than those generated with related QS saponin variants lacking the tucaresol motif. The conjugates retained potent adjuvant activity, low toxicity, and improved activity-toxicity profiles relative to QS-21 itself and induced IgG subclass profiles similar to those of QS-21, indicative of both Th1 cellular and Th2 humoral immune responses. This study opens the door to installation of other substituents at the terminus of the acyl chain domain to develop additional QS saponin conjugates with desirable immunologic properties.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: fernana2@mskcc.org.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Tejada
authors.affiliation: Pharmacology Graduate Program, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Chea
authors.affiliation: Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: George
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gardner
authors.affiliation: Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
authors.affiliation: Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: ragupatg@mskcc.org.
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Pharmacology Graduate Program, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: tand@mskcc.org.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Pharmacology Graduate Program, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001547:Benzaldehydes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007074:Immunoglobulin G / Q000032:analysis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012503:Saponins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D001547:Benzaldehydes; D001565:Benzoates; D007074:Immunoglobulin G; D012503:Saponins; C078785:saponin QA-21V1; C059629:tucaresol
keywords: Carbohydrates; Immunoadjuvant; Natural product; QS-21; Saponin conjugate; Tucaresol; Vaccine