Synthesis of Glycocluster-Tumor Antigenic Peptide Conjugates for Dendritic Cell Targeting

Abstract : The use of dendritic cells (DC) for the development of therapeutic cancer vaccines is attractive because of their unique ability to present tumor epitopes via the MHC class I pathway to induce cytotoxic CD8+ T lymphocyte responses. C-Type membrane lectins, DC-SIGN and the mannose receptor (MR), present on the DC surface, recognize oligosaccharides containing mannose and/or fucose and mediate sugar-specific endocytosis of synthetic oligolysine-based glycoclusters. We therefore asked whether a glycotargeting approach could be used to induce uptake and presentation of tumor antigens by DC. To this end, we designed and synthesized glycocluster conjugates containing a CD8+ epitope of the Melan-A/Mart-1 melanoma antigen. These glycocluster-Melan-A conjugates were obtained by coupling glycosynthons: oligosaccharyl-pyroglutamyl-beta-alanine derivatives containing either disaccharides, a dimannoside (Manalpha-6Man) or lactoside, or a Lewis oligosaccharide, to Melan-A 16-40 peptide comprising the 26-35 HLA-A2 restricted T cell epitope, extended with an oligolysine stretch at the C-terminal end. We showed by confocal microscopy and flow cytometry that fluorescent-labeled Melan-A glycoclusters containing either dimannoside or Lewis oligosaccharide were taken up by DC and concentrated in acidic vesicles; conversely lactoside glycopeptides were not at all taken up. Furthermore, using surface plasmon resonance, we showed that dimannoside and Lewis-Melan-A conjugates bind MR and DC-SIGN with high affinity. DC loaded with these conjugates, but not with the lactose-Melan-A conjugate, led to an efficient presentation of the Melan-A epitope eliciting a CD8+ T-lymphocyte response. These data suggest that synthetically designed glycocluster-tumor antigen conjugates may induce antigen cross-presentation by DC and represent a promising tool for the development of tumor vaccines.
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https://hal.archives-ouvertes.fr/hal-00166566
Contributor : Isabelle Frapart <>
Submitted on : Tuesday, August 7, 2007 - 12:29:28 PM
Last modification on : Thursday, November 22, 2018 - 2:38:11 PM

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Oruganti Srinivas, Pierre Larrieu, Eric Duverger, Claire Boccaccio, Marie-Thérèse Bousser, et al.. Synthesis of Glycocluster-Tumor Antigenic Peptide Conjugates for Dendritic Cell Targeting. Bioconjugate Chemistry, American Chemical Society, 2007, 18 (5), pp.1547-1554. ⟨10.1021/bc070026g⟩. ⟨hal-00166566⟩

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