Development of Globo-H cancer vaccine.

Abstract

The development of anticancer vaccines requires the identification of unique epitope markers, preferably expressed exclusively on the surface of cancer cells. This Account describes the path of development of a carbohydrate-based vaccine for metastatic breast cancer, including the selection and synthesis of Globo-H as the target, the development of the vaccine conjugate and adjuvant design, the study of the immune response and consideration of class switch, and the analysis of Globo-H distribution on the surface of various cancer cells, cancer stem cells, and normal cells. The first synthesis of Globo-H was accomplished through the use of glycal chemistry; this approach delivered sufficient material for evaluation in phase I human trials. The development of a programmable one-pot synthesis method rendered the synthesis more practical and enabled the midstage proof-of-concept phase II trial and late-stage phase III trial. Finally, enzymatic synthesis of Globo-H coupled with cofactor regeneration was used for the late-stage multicenter trials and manufacture of the product. Along this path of development, it was discovered that the vaccine induced antibodies to target not only Globo-H, but also SSEA3 and SSEA4. Moreover, these three glycolipids were found to be uniquely expressed not only on the cell surface of breast cancer but on 15 additional cancer types, suggesting the broad application of this vaccine in cancer treatment and perhaps cancer prevention. In addition, a new glycolipid adjuvant was designed to target the CD1d receptor on dendritic cells and B cells for presentation to and activation of T cells to modulate the immune response and induce a class switch from IgM to IgG, thereby overcoming the common problem of carbohydrate-based vaccines that often induce mainly IgM antibodies. As demonstrated in this vaccine development, the chemical approach to the synthesis and conjugation of carbohydrate-based immunogens provides the flexibility for access to various structures and linkers to identify optimal compositions for development. The enzymatic method was then introduced to enable the practical synthesis of the vaccine candidate for clinical development and commercialization. Overall, this Account illustrates the path of development of a cancer vaccine, from selection of a unique glycan marker on breast cancer cells and the cancer stem cells as target to the use of chemistry in combination with immunology and cancer biology to enable the design and development of the Globo-H vaccine to target three specific glycan markers exclusively expressed on the cell surface of a number of different types of cancer.