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Cancer Vaccines:
There are a variety of carbohydrates that have received attention as tumor antigens. These include gangliosides like GM2, GD2, GD3 expressed on melanomas, sarcomas and neuroblastomas, the Thomsen-Friedenreich antigen (TF), Tn and sialylated Tn (sTn) blood-group-related antigens that are expressed on mucins in a variety of epithelial cancers, fucosyl-GM1 expressed on small-cell lung cancers and the histo-blood group related Lewis antigens like Lewis Y and Globo H antigens also expressed on a variety of epithelial cancers. The restricted distribution of these antigens on normal tissues and their expression on malignancies suggest that these carbohydrate antigens are important targets for immunotherapy. Carbohydrate antigens however are T cell independent antigens. As such, they function as poor immunogens. As a means to convert carbohydrate T independent responses to T dependent responses we are pioneering the development of peptides that function as carbohydrate mimics. We have developed peptides that mimic bacterial, viral and tumor associated carbohydrates using a combination of screening random peptide display libraries and molecular modeling (structure assisted vaccine design). In this regard we have shown that it is possible to define peptides theoretically using computer-based approaches (bioinformatics) that validate those identified experimentally.
In terms of cancer vaccines, we are focusing on antigens associated with Breast, ovarian, colon, small cell lung cancers and melanoma. Peptides that mimic carbohydrate structure have significant advantages as vaccines. We have shown that peptide mimetic immunization leads to 1.) Consistently high titer tumor reactive IgM and IgG serum antibodies. 2.) Serum antibodies that mediate complement lysis of tumor cells in vitro. 3.) Serum antibodies that mediate the killing of target cells in xenografted animals. 4.) Serum antibodies that do not cross-reactive with normal tissues. and 5) activation of tumor reactive cellular responses in both prophylactic and therapeutic settings. Consequently, this approach constitutes a novel strategy in vaccine design for further reducing micrometastases and prevention of recurrence. We are moving toward testing these peptides in pilot trials in humans in the very near future.
Selected Publications:
Monzavi-Karbassi B, Stanley JS, Hennings L, Jousheghany F, Artaud C,
Shaaf S, Kieber-Emmons T. Chondroitin sulfate glycosaminoglycans
as major P-selectin ligands on metastatic breast cancer cell lines. Int
J Cancer. 2007;120(6):1179-91.
Pashov A, Perry M, Dyar M, Chow M, Kieber-Emmons T.
Defining carbohydrate antigens as HIV vaccine candidates. Curr Pharm
Des. 2007;13(2):185-201.
Hakkak R, MacLeod S, Shaaf S, Holley AW, Simpson P, Fuchs G, Jo CH,
Kieber-Emmons T, Korourian S. Obesity increases the incidence of
7,12-dimethylbenz(a)anthracene-induced mammary tumors in an
ovariectomized Zucker rat model. Int J Oncol. 2007;30(3):557-63.
Monzavi-Karbassi B, Hennings LJ, Artaud C, Liu T, Jousheghany F, Pashov
A, Murali R, Hutchins LF, Kieber-Emmons T. Preclinical studies of
carbohydrate mimetic peptide vaccines for breast cancer and melanoma.
Vaccine. 2007 Jan 26; [Epub ahead of print]
Pashov AD, Plaxco J, Kaveri SV, Monzavi-Karbassi B, Harn D,
Kieber-Emmons T. Multiple antigenic mimotopes of HIV carbohydrate
antigens: relating structure and antigenicity. J Biol Chem. 2006
281:29675-83.
Monzavi-Karbassi B,
Pashov A, Jousheghany F, Artaud C, Kieber-Emmons T.
Evaluating strategies to enhance the
anti-tumor immune response to a carbohydrate mimetic peptide vaccine.
Int J Mol Med. 2006 17:1045-52.
Carcel-Trullols J,
Stanley JS, Saha R, Shaaf S, Bendre MS, Monzavi-Karbassi B, Suva LJ,
Kieber-Emmons T. Characterization of the glycosylation profile of
the human breast cancer cell line, MDA-231, and a bone colonizing
variant. Int J Oncol. 2006. 28:1173-83.
Whitehead, T.L.;
Kieber-Emmons, T. Applications of in vitro NMR spectroscopy and
1H-NMR metabonomics to breast cancer characterization and detection,
Prog. NMR Spectroscopy 2005, 47, 165-174.
Whitehead, T.L, Monzavi-Karbassi, B., Kieber-Emmons, T., 1H-NMR
metabonomics analysis of sera differentiates between mammary tumor
bearing mice and healthy controls.
Metabolomics, 2005;
1 (3) 269-278.
Hakkak R, Holley AW, MacLeod SL, Simpson PM, Fuchs GJ, Jo CH,
Kieber-Emmons T, Korourian S.,
Obesity promotes
7,12-dimethylbenz(a)anthracene-induced mammary tumor development
in female zucker rats. Breast Cancer Research 2005, 7:R627-R633.
Pashov A, Canziani,
G., Monzavi-Karbassi, B., Kaveri, S., Macleod S, Saha R, Perry M,
Vancott TC, Kieber-Emmons, T. Antigenic properties of peptide
mimotopes of HIV-1 associated carbohydrate antigens. J Biol Chem. 2005;
280:28959-65.
Monzavi-Karbassi B, Cunto-Amesty G, Luo P, Kieber-Emmons T.
Peptide mimotopes of carbohydrate antigens in vaccine discovery. Trends
in Biotech. 2002; 20 (5): 207-14.
Cunto-Amesty G, Luo P, Monzavi-Karbassi B, Lees A, Kieber-Emmons T.
Exploiting Molecular Mimicry to Broaden the Immune Response to
Carbohydrate Antigens for Vaccine Development. Vaccine 2001.
19:2361-2368.
Cunto-Amesty G, Dam TK, Luo P, Monzavi-Karbassi B, Brewer CF, VanCott TC,
Kieber-Emmons T. Directing the Immune Response to Carbohydrate
Antigens, J. Biol. Chem. 2001. 276:30490-30498.
Monzavi-Karbassi B, Cunto-Amesty G, Luo P, Shamloo S, Blaszcyk-Thurin,
M, Kieber-Emmons T. Immunization with a Carbohydrate Mimicking
Peptide Augments Tumor-Specific Cellular Responses. International
Immunology 2001. 13:1361-5.
Monzavi-Karbassi B, Kieber-Emmons T. Current concepts in cancer
vaccine design. Biotechniques. 2001, 30:170-176.
Luo P, Canziani G, Cunto-Amesty G, Kieber-Emmons T. A Molecular
Basis for Functional Peptide Mimicry of a Carbohydrate Antigen. J. Biol.
Chem. 2000; 275:16146-16154.
Kieber-Emmons T, Monzavi-Karbassi B, Wang B, Luo P, Weiner DB.
DNA immunization with minigenes of carbohydrate mimotopes induce
functional anti-carbohydrate antibody response. J Immunol: Cutting Edge.
2000; 165:623-627.
Kohler H, Kaveri S, Kazatchkine M, Kieber-Emmons T. Natural
Selection Theory Revisited. Immunologist, 2000, 8: 91-93. |
