Induction of a Melanoma‐Specific Antibody Response by a Monovalent, but not a Divalent, Synthetic GM2 Neoglycopeptide

Abstract

The GM2 ganglioside represents an important target for specific anticancer immunotherapy. We designed and synthesized a neoglycopeptide immunogen displaying one or two copies of the GM2 tetrasaccharidic moiety. These glycopeptides were prepared using the Huisgen cycloaddition, which enables the efficient ligation of the alkyne-functionalized biosynthesized GM2 with an azido CD4(+) T cell epitope peptide. It is worth noting that the GM2 can be produced on a gram scale in bacteria, which can be advantageous for a scale-up of the process. We show here for the first time that a fully synthetic glycopeptide, which is based on a ganglioside carbohydrate moiety, can induce human tumor cell-specific antibodies after immunization in mice. Interestingly, the monovalent, but not the divalent, form of GM2 peptide construct induced antimelanoma antibodies. Unlike traditional vaccines, this vaccine is a pure chemically-defined entity, a key quality for consistent studies and safe clinical evaluation. Therefore, such carbohydrate-peptide conjugate represents a promising cancer vaccine strategy for active immunotherapy targeting gangliosides.

Translating Tumor Antigens into Cancer Vaccines

“…In particular, keyhole limpet hemocyanin (KLH) has been shown to be the most effective carrier for TACAs (86), and KLH conjugates of GM2 for melanoma (27) as well as those of sTn for breast cancer (73) have both entered phase III clinical trials. However, the disappointing outcomes of these vaccine clinical trials, in terms of time-to-disease progression and overall survival, have driven the generation of several forms of fully synthetic carbohydrate vaccines, which have been shown to be immunogenic regardless of the use of a protein carrier or external adjuvant (6,13,22,76,176,194). Unfortunately, despite all efforts, TACA-based cancer vaccines have failed to induce sufficient T cell-mediated immune responses in cancer patients, and none has been approved for clinical use yet (64).…”

Recent progress in the field of neoglycoconjugate chemistry

“…Whereas S-linked analogs achieved a two-fold improvement of the therapeutic index (84) in comparison with the natural component, similar triazole-linked analogs showed more than six-fold increase in therapeutic index (78). Triazole-linked analogs were also considered as an alternative approach to obtain GM2 glycoconjugate vaccines, avoiding the limitations derived from the traditional hemisynthetic strategy (81). Other neoglycopeptides, e.g., S-linked glycoconjugates containing tumorassociated carbohydrate antigens, were synthesized and considered also as potential drugs in cancer vaccine therapies (86).…”

Multivalent glycoconjugates in medicinal chemistry

“…This is considered the first report on the induction of human tumor cell-specific antibodies after immunization with a synthetic glycopeptide. 69 Danishefsky et al have developed glycoconjugated vaccines that are useful for the treatment of cancer and effective at inducing antibodies against all carbohydrate antigens present on the glycoconjugates. For example, vaccine shown in Fig.…”