Induction of carbohydrate‐specific antibodies in HLA‐DR transgenic mice by a synthetic glycopeptide: a potential anti cancer vaccine for human use

TLDR

Anticancer immunotherapy is rapidly advancing, and synthetic tumor‑associated carbohydrate antigens hold promise for targeted responses, but their clinical translation is limited by HLA polymorphism. The study aimed to create a glycopeptide vaccine that elicits a T‑cell dependent anti‑carbohydrate response while bypassing HLA polymorphism by linking a Tn antigen epitope to universal PADRE and CEA CTL epitopes. The vaccine’s immunogenicity was tested in outbred mice and HLA‑DR1/DR4 transgenic mice. The glycopeptide induced robust T‑cell dependent antibodies against the Tn antigen in both outbred and HLA‑transgenic mice, and these antibodies effectively recognized a human tumor cell line, underscoring the construct’s potential as a human anticancer vaccine.

Abstract

Over the last few years, anticancer immunotherapy has emerged as a new exciting area for controlling tumors. In particular, vaccination using synthetic tumor-associated antigens (TAA), such as carbohydrate antigens hold promise for generating a specific antitumor response by targeting the immune system to cancer cells. However, development of synthetic vaccines for human use is hampered by the extreme polymorphism of human leukocyte-associated antigens (HLA). In order to stimulate a T-cell dependent anticarbohydrate response, and to bypass the HLA polymorphism of the human population, we designed and synthesized a glycopeptide vaccine containing a cluster of a carbohydrate TAA B-cell epitope (Tn antigen: alpha-GalNAc-Ser) covalently linked to peptides corresponding to the Pan DR 'universal' T-helper epitope (PADRE) and to a cytotoxic T lymphocyte (CTL) epitope from the carcinoembryonic antigen (CEA). The immunogenicity of the construct was evaluated in outbred mice as well as in HLA transgenic mice (HLA-DR1, and HLA-DR4). A strong T-cell dependent antibody response specific for the Tn antigen was elicited in both outbred and HLA transgenic mice. The antibodies induced by the glycopeptide construct efficiently recognized a human tumor cell line underlying the biological relevance of the response. The rational design and synthesis of the glycopeptide construct presented herein, together with its efficacy to induce antibodies specific for native tumor carbohydrate antigens, demonstrate the potential of a such synthetic molecule as an anticancer vaccine candidate for human use.