title: Synthesis and immunological properties of N-modified GM3 antigens as therapeutic cancer vaccines.
abstract: The problem of immunotolerance to GM3, an important tumor-associated trisaccharide antigen, seriously hinders its usage in cancer vaccine development. To solve this problem, the keyhole limpet hemocyanin (KLH) conjugates of a series of GM3 derivatives were synthesized and screened as therapeutic cancer vaccines. First, the beta-linked anomeric azides of differently N-acylated GM3 analogues were prepared by a highly convergent procedure. Next, a pentenoyl group was linked to the reducing end of the carbohydrate antigens following selective reduction of the azido group. The linker was thereafter ozonolyzed to give an aldehyde functionality permitting the conjugation of the antigens to KLH via reductive amination. Finally, the immunological properties of the resultant glycoconjugates were studied in C57BL/6 mice by assessing the titers of specific antibodies induced by the GM3 analogues. While KLH-GM3 elicited low levels of immune response, the KLH conjugates of N-propionyl, N-butanoyl, N-iso-butanoyl, and N-phenylacetyl GM3s induced robust immune reactions with antibodies of multiple isotypes, indicating significantly improved and T-cell dependent immune responses that lead to isotype switching, affinity maturation, and the induction of immunological "memory". It was suggested that GM3PhAc-KLH is a promising vaccine candidate for glycoengineered immunotherapy of cancer with GM3 as the primary target.
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Pan
authors.forename: Peter
authors.initials: P
authors.lastname: Chefalo
authors.forename: Nancy
authors.initials: N
authors.lastname: Nagy
authors.forename: Clifford
authors.initials: C
authors.lastname: Harding
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000138:chemical synthesis* / Q000276:immunology; D002240:Carbohydrate Sequence; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000276:immunology; D006433:Hemocyanins / Q000737:chemistry*; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D007129:Immunoglobulin Gm Allotypes / Q000737:chemistry* / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D006001:Glycoconjugates; D007074:Immunoglobulin G; D007129:Immunoglobulin Gm Allotypes; D007075:Immunoglobulin M; D018074:Vaccines, Conjugate; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin