Anti-Tumor Immunity Provided by a Synthetic Multiple Antigenic Glycopeptide Displaying a Tri-Tn Glycotope

Abstract

In many cancer cells the alteration of glycosylation processes leads to the expression of cryptic carbohydrate moieties, which make them good targets for immune intervention. Identification of cancer-associated glycotopes as well as progress in chemical synthesis have opened up the way for the development of fully synthetic immunogens that can induce anti-saccharide immune responses. Here, we synthesized a dendrimeric multiple antigenic glycopeptide (MAG) containing the Tn Ag O-linked to a CD4+ T cell epitope. This MAG is based on three consecutive Tn moieties (tri-Tn) corresponding to the glycotope recognized by an mAb (MLS 128) produced against the LS180 colon carcinoma cell line. The Abs induced by this MAG recognized murine and human tumor cell lines expressing the Tn Ag. Prophylactic vaccination using MAG provided protection of mice against tumor challenge. When used in active specific immunotherapy, the MAG carrying the tri-Tn glycotope was much more efficient than the mono-Tn analogue in promoting the survival of tumor-bearing mice. Furthermore, in active specific immunotherapy, a linear glycopeptide carrying two copies of the tri-Tn glycotope was shown to be poorly efficient compared with the dendrimeric MAG. Therefore, both the clustering of carbohydrate Ags and the way they are displayed seem to be important parameters for stimulating efficient anti-saccharide immune responses.

Mouse-Human Chimeric Anti-Tn IgG1 Induced Anti-tumor Activity against Jurkat Cells in Vitro and in Vivo

“…The spleen was removed 3 d after final injection of the antigen, and 2ϫ10 8 splenocytes fused with 2ϫ10 7 P3-U1 in the presence of polyethylene glycol 1000 (Junsei, Tokyo, Japan). Cultured hybridoma cells in wells showing anti-Tn antibody activity were screened by 8200 cellular detection system (Applied Biosystems, Tokyo, Japan), using Lec8 and DG44 as target cells.…”

“…And active immunotherapy, using vaccines targeted towards Tn-antigen, has already been evaluated with promising results. [8][9][10] Over the last decade, monoclonal antibody therapy has been established as an effective treatment against cancer. At an early stage, murine monoclonal antibodies were used clinically, but severe immunogenicity and modest effector function limited their usefulness.…”

Tn Glycosylation of the MUC6 Protein Modulates Its Immunogenicity and Promotes the Induction of Th17-biased T Cell Responses

“…The involvement of mucins and their associated carbohydrate antigens (e.g. Tn antigen) in the metastatic process of tumor cells makes them relevant targets for the prevention of metastasis and recurrence of cancers by therapeutic vaccination (8,9).…”

Synthesis and Immunological Evaluation of Self‐Assembling and Self‐Adjuvanting Tricomponent Glycopeptide Cancer‐Vaccine Candidates

“…The O-acetate protecting groups on the glycan units were subsequently removed by treatment with hydrazine hydrate. [19] The target MUC1 (glyco)peptides 4--6 were purified by reversed-phase HPLC and isolated in 14--45^% yield, based on the original resin loading.…”