Fully synthetic carbohydrate-based cancer vaccines
The Boons group was the first to design, chemically synthesize and immunologically evaluate fully synthetic carbohydrate-based multi-component vaccines to overcome the poor immunogenicity of tumor-associated carbohydrate and glycopeptide antigens. A large number of carcinomas exhibits a striking overexpression of the mucin MUC1 resulting in a loss of polarization and altered glycosylation. Although it has been realized that MUC1 is one of the most attractive targets for cancer vaccine development, it has been difficult to design a vaccine candidate that can elicit relevant humoral and cellular immunity. We have designed, chemically synthesized and immunologically evaluated a range of fully synthetic compounds, which made it possible to identify the minimum requirements to consistently induce cytotoxic IgG antibodies and cytotoxic T-lymphocytes resulting in a therapeutic response in a humanized mouse model of mammary cancer. These studies provide a firm foundation to initiate clinical studies. In addition, we have developed a method to attach in a site-specific manner cytotoxic drugs to antibodies for antibody drug development.
Supekar NT, Lakshminarayanan V, Capicciotti C, Sirohiwal A, Madsen CS, Wolfert MA, Cohen PA, Gendler SJ, Boons GJ (2018) Synthesis and immunological evaluation of a multicomponent cancer vaccine candidate containing a long MUC1 glycopeptide. ChemBioChem 19(2):121-125.
Lakshminarayanan V, Supekar NT, Wei J, McCurry DB, Dueck AC, Kosiorek HE, Trivedi PP, Bradley JM, Madsen CS, Pathangey LB, Hoelzinger D, Wolfert MA, Boons GJ, Cohen PA, Gendler SJ (2016) MUC1 vaccines, comprised of glycosylated or non-glycosylated peptides or tumor-derived MUC1, can circumvent immunoediting to control tumor growth in MUC1 transgenic mice. PLoS ONE 11(1):e0145920.
Thompson P, Lakshminarayanan V, Supekar NT, Bradley JM, Cohen PA, Wolfert MA, Gendler SJ, Boons GJ (2015) Linear synthesis and immunological properties of a fully synthetic vaccine containing a sialylated MUC1 glycopeptide. Chem Commun 51(50):10214-10217.
Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM, Pathangey LB, Madsen CS, Cohen PA, Gendler SJ, Boons GJ (2012) Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proc Natl Acad Sci USA 109(1):261-266.