title: Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses.
abstract: Generation of a CD8(+) response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8(+) T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8(+) T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an l-Rhamnose (Rha) epitope. We synthesized a 20-amino-acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated α-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper(I)-catalyzed azido-alkyne cycloaddition (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo , 2801 West Bancroft Street, Toledo, Ohio 43606, United States.
authors.forename: Partha
authors.initials: P
authors.lastname: Karmakar
authors.affiliation: Department of Medicinal and Biological Chemistry, The University of Toledo Health Science Campus , 3000 Arlington Avenue, Toledo, Ohio 43614, United States.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo , 2801 West Bancroft Street, Toledo, Ohio 43606, United States.
authors.forename: Sourav
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Medicinal and Biological Chemistry, The University of Toledo Health Science Campus , 3000 Arlington Avenue, Toledo, Ohio 43614, United States.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Wall
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo , 2801 West Bancroft Street, Toledo, Ohio 43606, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sucheck
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D049109:Cell Proliferation; D060326:Chemistry Techniques, Synthetic; D002784:Cholesterol / Q000737:chemistry; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008810:Mice, Inbred C57BL; D018396:Mucin-1 / Q000737:chemistry* / Q000276:immunology; D015202:Protein Engineering / Q000379:methods; D012210:Rhamnose / Q000276:immunology*; D014612:Vaccines / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D018796:Immunoconjugates; D008081:Liposomes; D018396:Mucin-1; D014612:Vaccines; D007371:Interferon-gamma; D002784:Cholesterol; D012210:Rhamnose