title: Development of a minimal saponin vaccine adjuvant based on QS-21.
abstract: Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.
authors.affiliation: Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Tejada
authors.affiliation: Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Chea
authors.affiliation: Melanoma & Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: George
authors.affiliation: Radiochemistry & Imaging Science Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: NagaVaraKishore
authors.initials: N
authors.lastname: Pillarsetty
authors.affiliation: Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gardner
authors.affiliation: 1] Melanoma & Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [2].
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
authors.affiliation: Melanoma & Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.affiliation: Radiochemistry & Imaging Science Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: 1] Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [2] Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [3] Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
authors.affiliation: 1] Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [2] Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [3] Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA [4].
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D012503:Saponins / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D014612:Vaccines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000276:Adjuvants, Immunologic; D012503:Saponins; D014612:Vaccines; C078785:saponin QA-21V1