Tumor-associated carbohydrate antigens (TACAs) are saccharides and oligosaccharides which show highly restricted expression on cancer cells. Since TACAs are unique to cancer cells, there is a great interest in generating an active immune response against TACAs as a means of reducing cancer metastasis or recurrence. Two major challenges to using TACAs in active immunotherapy are their poor antigenicity and the inherent difficulty of synthesizing oligosaccharides and related glycoconjugates by chemical means. Past work demonstrated that liposomal vaccines with a TACA- bearing peptide can generate immune responses to TACAs. If the liposome contains a xenobiotic carbohydrate such as rhamnose, natural antibodies against the carbohydrate will greatly enhance the generation of an immune response, presumably through Fc mediated antigen uptake. The first specific aim of this proposal seeks to determine in more detail the mechanism of enhancement by studying purified human anti-rhamnose antibodies and their role in antigen uptake in wild type and Fc humanized mice. The second specific aim will determine if a specific Fc region can serve as a more generally effective targeting ligand than rhamnose for this vaccine. The most effective vaccine formulation will be tested in humanized mice to better predict its efficacy in humans. Stimulation of invariant natural killer T cells by certain ceramides can serve as a vaccine adjuvant. The third specific aim involves synthesis of rhamnose-modified ceramides and determining if they can serve as improved vaccine adjuvants through binding to CD1d in addition to providing a recognition site for natural antibodies. This proposal takes advantage of a collaborative interaction between researchers trained in organic chemistry and immunology so that the structure and antigenicity of all vaccines will be well characterized in wild type mice an in mice bearing humanized immune cells.

Public Health Relevance

This project will develop and evaluate the cellular and humoral immune response to synthetic vaccines in mice that will serve as leads for human anti-cancer vaccines. Chemical approaches will be developed that will aid in increasing the ability of the vaccines to stimulate the immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15GM094734-02
Application #
8878565
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Marino, Pamela
Project Start
2011-05-01
Project End
2018-04-30
Budget Start
2015-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Toledo
Department
Biochemistry
Type
Schools of Pharmacy
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Vartak, Abhishek; Hefny, Fatma M; Sucheck, Steven J (2018) Synthesis of Oligosaccharide Components of the Outer Core Domain of P. aeruginosa Lipopolysaccharide Using a Multifunctional Hydroquinone-Derived Reducing-End Capping Group. Org Lett 20:353-356
Hossain, Md Kamal; Vartak, Abhishek; Karmakar, Partha et al. (2018) Augmenting Vaccine Immunogenicity through the Use of Natural Human Anti-rhamnose Antibodies. ACS Chem Biol 13:2130-2142
Vartak, Abhishek; Sucheck, Steven J (2016) Recent Advances in Subunit Vaccine Carriers. Vaccines (Basel) 4:
Hossain, Md Kamal; Wall, Katherine A (2016) Immunological Evaluation of Recent MUC1 Glycopeptide Cancer Vaccines. Vaccines (Basel) 4:
Karmakar, Partha; Lee, Kyunghee; Sarkar, Sourav et al. (2016) Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses. Bioconjug Chem 27:110-20
Long, David E; Karmakar, Partha; Wall, Katherine A et al. (2014) Synthesis of ?-L-rhamnosyl ceramide and evaluation of its binding with anti-rhamnose antibodies. Bioorg Med Chem 22:5279-89
Bouhall, Samantha K; Sucheck, Steven J (2014) In situ preactivation strategies for the expeditious synthesis of oligosaccharides: A review. J Carbohydr Chem 33:347-367
Gaitonde, Vishwanath; Lee, Kyunghee; Kirschbaum, Kristin et al. (2014) Bio-Based Bisfuran: Synthesis, Crystal Structure and Low Molecular Weight Amorphous Polyester. Tetrahedron Lett 55:4141-4145
Sarkar, Sourav; Salyer, Alex C D; Wall, Katherine A et al. (2013) Synthesis and immunological evaluation of a MUC1 glycopeptide incorporated into l-rhamnose displaying liposomes. Bioconjug Chem 24:363-75
Ibrahim, Diaa A; Boucau, Julie; Lajiness, Daniel H et al. (2012) Design, synthesis, and X-ray analysis of a glycoconjugate bound to Mycobacterium tuberculosis antigen 85C. Bioconjug Chem 23:2403-16

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