The over-expression of oligosaccharides such as Globo-H, LewisY, Tn and STn is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccine development has been complicated by difficulties of eliciting high titers of IgG antibodies against classical conjugates of tumor-associated carbohydrates to carrier proteins. We have designed, chemical synthesized and immunologically evaluated a number of fully synthetic vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. We have found that a three-component vaccine composed of a TLR2 agonist, a promiscuous peptide T-helper epitope and a tumor-associated glycopeptides, can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor-associated carbohydrate. The superior properties of the vaccine candidate are attributed to the local production of cytokines, upregulation of co-stimulatory proteins, enhanced uptake by macrophages and dendritic cells, and avoidance of epitope suppression. An important aim of the competitive renewal is to further develop the fully synthetic multi-component vaccine candidates by examining various in-build adjuvants, employ foreign and MUC1-derived helper T- epitopes and use carbohydrates of increasing complexity. Our central hypothesis is that these parameters critically modulate humoral and cellular immune responses and can only be optimized by detailed structure- activity relationship studies. Furthermore, by examining the influence of glycosylation on intracellular trafficking, processing and presentation of (glyco)peptides by MHC-I and MHC-II we hope to establish general design principles for multi-component (glyco)peptide-based vaccines. At the completion of the proposed studies we expected to have laid a firm foundation for a phase I/II clinical trial. We will also employ the multi-component immunogen technology for generating glycopeptide-specific monoclonal antibodies (MAbs) for various glycoforms of MUC1, which we expect to utilize to determine glycoforms expressed by tumor tissue. In this respect, there is a lack of well-characterized glycopeptide- specific MAbs for important epitopes of MUC1. Such reagents are, however, required for future personalized immuno-therapy in which the structure of the saccharide moiety of a multi-component cancer vaccine is tailored to the saccharide expression by cancerous tissue. Furthermore, well-defined MAbs are also required for basic cancer research and, for example, are needed for evaluation of carbohydrate expression in an animal model for vaccine evaluation. Finally, we will develop a suite of Cu-free click reagents for cancer marker discovery and studying processing of synthetic antigens.

Public Health Relevance

Tumor progression is intimately associated with the appearance of unusual carbohydrates on the surface of cells. Although it has been realized that this abnormal expression can be exploited for cancer vaccine design, carbohydrate-based cancer vaccine development has been complicated by the difficulty of eliciting robust immune responses in most patients. We are developing fully synthetic multi-component vaccine candidates that can overcome the poor immunogenicity of tumor-associated carbohydrates and offer a prospect for use in cancer immune therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088986-10
Application #
8258735
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
2011-05-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$357,619
Indirect Cost
$116,798
Name
University of Georgia
Department
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
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Li, Xiuru; Fang, Tao; Boons, Geert-Jan (2014) Preparation of well-defined antibody-drug conjugates through glycan remodeling and strain-promoted azide-alkyne cycloadditions. Angew Chem Int Ed Engl 53:7179-82
Arumugam, Selvanathan; Guo, Jun; Mbua, Ngalle Eric et al. (2014) Selective and Reversible Photochemical Derivatization of Cysteine Residues in Peptides and Proteins. Chem Sci 5:1591-1598
Ledin, Petr A; Kolishetti, Nagesh; Hudlikar, Manish S et al. (2014) Exploring strain-promoted 1,3-dipolar cycloadditions of end functionalized polymers. Chemistry 20:8753-60
Abdel-Aal, Abu-Baker M; Lakshminarayanan, Vani; Thompson, Pamela et al. (2014) Immune and anticancer responses elicited by fully synthetic aberrantly glycosylated MUC1 tripartite vaccines modified by a TLR2 or TLR9 agonist. Chembiochem 15:1508-13

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