On the power of chemical synthesis: Immunological evaluation of models for multiantigenic carbohydrate-based cancer vaccines Journal Article

   


Authors: Ragupathi, G.; Coltart, D. M.; Williams, L. J.; Koide, F.; Kagan, E.; Allen, J.; Harris, C.; Glunz, P. W.; Livingston, P. O.; Danishefsky, S. J.
Article Title: On the power of chemical synthesis: Immunological evaluation of models for multiantigenic carbohydrate-based cancer vaccines
Abstract: Synthetic carbohydrate cancer vaccines have been shown to stimulate antibody-based immune responses in both preclinical and clinical settings. The antibodies have been observed to react in vitro with the corresponding natural carbohydrate antigens expressed on the surface of tumor cells, and are able to mediate complement-dependent and/or antibody-dependent cell-mediated cytotoxicity. Furthermore, these vaccines have proven to be safe when administered to cancer patients. Until recently, only monovalent antigen constructs had been prepared and evaluated. Advances in total synthesis have now enabled the preparation of multivalent vaccine constructs, which contain several different tumor-associated carbohydrate antigens. Such constructs could, in principle, serve as superior mimics of cell surface antigens and, hence, as potent cancer vaccines. Here we report preclinical ELISA-based evaluation of a TF-Ley-Tn bearing construct (compound 3) with native mucin glycopeptide architecture and a Globo-H-Ley-Tn glycopeptide (compound 4) with a nonnative structure. Mice were immunized with one or the other of these constructs as free glycopeptides or as keyhole lymphet hemocyanin conjugates. Either QS-21 or the related GPI-0100 were coadministered as adjuvants. Both keyhole lymphet hemocyanin conjugates induced IgM and IgG antibodies against each carbohydrate antigen, however, the mucin-based TF-Ley-Tn construct was shown to be less antigenic than the unnatural Globo-H-Ley-Tn construct. The adjuvants, although related, proved significantly different, in that GPI-0100 consistently induced higher titers of antibodies than QS-21. The presence of multiple glycans in these constructs did not appear to suppress the response against any of the constituent antigens. Compound 4, the more antigenic of the two constructs, was also examined by fluorescence activated cell sorter analysis. Significantly, from these studies it was shown that antibodies stimulated in response to compound 4 reacted with tumor cells known to selectively express the individual antigens. The results demonstrate that single vaccine constructs bearing several different carbohydrate antigens have the potential to stimulate a multifaceted immune response.
Keywords: controlled study; unclassified drug; human cell; drug safety; nonhuman; antigen expression; mouse; animals; mice; cell line; animal experiment; drug potency; animalia; membrane antigen; immune response; molecular sequence data; antigens; cancer vaccine; cancer vaccines; immunogenicity; vaccines, synthetic; cell membrane; immunological adjuvant; molecular structure; adjuvants, immunologic; fluorescence activated cell sorting; antibody; immunoglobulin g antibody; synthesis; carbohydrate sequence; carbohydrates; carbohydrate antigen; glycan derivative; glycopeptide; antibody formation; antibody titer; drug formulation; complement dependent cytotoxicity; keyhole limpet hemocyanin; gpi 0100; immunoglobulin m antibody; vaccines, conjugate; le(y) antigen; qs 21; models, immunological; conjugate vaccines; humans; human; priority journal; article; polyvalent vaccines; multivalent; synthetic vaccines
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 99
Issue: 21
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2002-10-15
Start Page: 13699
End Page: 13704
Language: English
DOI: 10.1073/pnas.202427599
PUBMED: 12359877
PROVIDER: scopus
PMCID: PMC129747
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-0037108769&partnerID=40&md5=2ce28192ae98336606ae343e2ef45e58
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Don Coltart
    6 Coltart
  2. Fusataka Koide
    14 Koide
  3. Jennifer R Allen
    11 Allen
  4. Peter W Glunz
    11 Glunz
  5. Christina R Harris
    13 Harris
  6. Lawrence J Williams
    14 Williams
  7. Govindaswami Ragupathi
    144 Ragupathi
  8. Samuel J Danishefsky
    539 Danishefsky
  9. Philip O Livingston
    228 Livingston
  10. Ella Kagan
    9 Kagan
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