Département de chimie moléculaire

Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few mols. achieve this target without utilizing external immuno-adjuvants. In this study, the authors explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP mol. was constructed by synthesizing a chimeric peptide made of a CD8+ T cell epitope, from ovalbumin (OVA257-264) and an universal CD4+ T helper (Th) epitope (PADRE). The resulting CTL-Th peptide backbones was coupled to a carbohydrate B cell epitope based on a regioselectively addressable functionalized templates (RAFT), made of four $\alpha$-GalNAc mols. at C-terminal. The N terminus of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic external immuno-adjuvants. The final prototype OVA-GLP mol., delivered in adjuvant-free PBS, in mice induced: (1) robust RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA257-264-specific IFN-$\gamma$ producing CD8+ T cells; (3) PADRE-specific CD4+ T cells; (4) OVA-GLP vaccination elicited a redn. of tumor size in mice inoculated with syngeneic murine MO5 carcinoma cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the growth of pre-established MO5 tumors. The authors' results suggest self-adjuvanting glyco-lipopeptide mols. as a platform for B Cell, CD4+, and CD8+ T cell epitopes-based immunotherapeutic cancer vaccines. [on SciFinder(R)]