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Abstract
Cancer is one of the leading causes of deaths worldwide. Cancer results from a number of molecular events that changes the normal functions of the cells. In tumor cells, the natural control system that prevents cell overgrowth and invasion to other tissues are inactivated leading to its spread to other parts of the body. For many cancer types, combination therapy is the best approach, in which surgery or radiation therapy is performed to treat locally confined cancer followed by chemotherapy which kills the tumor cells that have spread to other parts of the body. However, one of the major drawbacks of these treatments is that they affect healthy cells along with cancer cells. Due to the recent advances in the field of cancer biology and immunology, new strategies such as hormone therapy, stem cell transplant and immunotherapy have evolved as alternative treatments. The mucin MUC1 is a large glycoprotein that is expressed on the apical surface of normal epithelial cells and highly over-expressed in various tumors, including colon, ovarian, and breast cancers. Therefore, MUC1 is an important target for the development of antitumor vaccines. A predominant characteristic of MUC1 is the VNTR region in its extracellular domain. The VNTR region is comprised of repeating units of a 20-amino acid sequence (APGSTAPPAHGVTSAPDTRP). In healthy epithelia, the VNTR is highly glycosylated on serine and threonine with long and branched O-linked carbohydrates while the cancerous cells express short and truncated TACAs such as Tn and STn. In this presented study we have reported multicomponent full-length MUC1 based cancer vaccine candidates that are capable of inducing humoral and cellular immunity against the tumor-associated MUC1, producing CTLs and ADCC-mediating antibodies. These vaccine candidates consist of a full-length MUC1 glycopeptide bearing one or more Tn antigens and contain immunodominant peptide motifs (PDTRP and PPAHGV) of MUC1 and a built-in immunoadjuvant, TLR2 ligand Pam3CysSK4. In this research, we have successfully utilized the highly efficient microwave-assisted solid phase synthesis protocols for linear synthesis of mono-and multi-glycosylated vaccine candidates. However, immunological evaluation of some of the cancer vaccine candidates is still underway.