Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors Journal Article


Authors: Keding, S. J.; Danishefsky, S. J.
Article Title: Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors
Abstract: Vaccines derived from totally synthetic carbohydrate antigens have been shown to elicit an immune response in both preclinical and clinical settings. The vaccines have been proven safe when administered in human clinical trials and are also competent at inducing antibodies that react with aberrant cells expressing the corresponding carbohydrate antigen. The most well studied vaccines have hitherto focused on single carbohydrate antigens, notwithstanding the known heterogeneity of transformed cells. Advances in synthetic organic chemistry have enabled the preparation and subsequent investigation of vaccines that contain several different tumor-associated carbohydrate antigens in a single molecule. These unimolecular constructs could, in principle, serve as superior mimics of cell surface antigens and hence, as multifaceted cancer vaccines. We report here the synthesis of a pentameric vaccine targeting a specific cancer. The new vaccine contains prostate tumor-associated antigens, Tn, TF, STn, Lewisy, and Globo-H. To reach our goal, antigen-containing amino acid monomers were assembled in a linear fashion to form a glycopeptide containing the five distinct carbohydrate antigen units. The attachment of a linker to the glycopeptide followed by an extraordinary global deprotection and subsequent conjugation to two different immunogenic carriers, keyhole limpet hemocyanin and N-α-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-L- cysteine, resulted in the vaccine constructs. The results described herein indicate that complex unimolecular multivalent vaccines can be efficiently produced in the laboratory. These fully synthetic vaccines have the potential to stimulate a multifaceted immune response against prostate cancer.
Keywords: unclassified drug; review; drug safety; drug synthesis; tumor antigen; prostate cancer; prostatic neoplasms; immune response; molecular sequence data; cancer vaccine; cancer vaccines; cell transformation; molecular structure; antigens, tumor-associated, carbohydrate; carbohydrate sequence; carbohydrate antigen; glycopeptide; stn antigen; tn antigen; cysteine; keyhole limpet hemocyanin; organic chemistry; hemocyanin; vaccines, conjugate; neoplasms, glandular and epithelial; equilenin; tf antigen; cancer immunology; lipoproteins; palmitic acid derivative; blood group lewis system; humans; male; priority journal; ciguatoxin; n alpha palmitoyl [2,3 bis(palmitoyloxy)propyl]cysteine
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 101
Issue: 33
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2004-08-17
Start Page: 11937
End Page: 11942
Language: English
DOI: 10.1073/pnas.0401894101
PROVIDER: scopus
PMCID: PMC514412
PUBMED: 15280546
DOI/URL:
Notes: Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):71 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus
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  1. Stacy J Keding
    9 Keding