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A Dissertation Entitled Approaches to Increase the Immunogenicity Of A Dissertation entitled Approaches to Increase the Immunogenicity of Carbohydrate Antigens Using PS A1 and Subsequent Immunotherapies by Kevin R. Trabbic Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry _________________________________________ Dr. Peter R. Andreana, Committee Chair _________________________________________ Dr. Ronald E. Viola, Committee Member _________________________________________ Dr. Katherine A. Wall, Committee Member _________________________________________ Dr. Amanda C. Bryant-Friedrich, Committee Member _________________________________________ Dr. Amanda C. Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2016 Copyright 2016, Kevin Roland Trabbic This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Approaches to Increase the Immunogenicity of Carbohydrate Antigens Using PS A1 and Subsequent Immunotherapies by Kevin R. Trabbic Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry The University of Toledo August 2016 Zwitterionic polysaccharides (ZPS) are emerging as a viable alternative to protein carriers for vaccines and immunotherapeutics. PS A1 and PS B from Bacteroides fragilis (ATCC® 25285™/NTTC® 9343™) are natural, zwitterionic carbohydrate-based polymers that can generate a CD4+ T cell mediated immune response and have recently been investigated as T cell carriers for tumor associated carbohydrate antigens (TACAs). TACAs represent suitable targets for cancer immunotherapies because, they are expressed on virtually all cancers and are known to be weakly immunogenic. The immune response to TACAs can be increased by conjugation to immunogenic materials such as proteins or lipids. Therefore, we hypothesize using ZPS as immunogenic carriers for TACAs, can augment the immune response by generating entirely carbohydrate specific antibodies. The rationale behind this carbohydrate-based construct was to fine- tune the immune response to target carbohydrate specific lectins and generate antibodies that exclusively recognize carbohydrates without the background binding to proteins or peptides, a long outstanding problem in increasing immunogenicity. To take advantage iii of the unique immune response to ZPS, we aimed to generate immunotherapies to target tumor glycosides. In previous work emanating from our group, the Thomsen-Nouveau (Tn antigen, α-D-GalNAc) was conjugated to PS A1, creating an entirely carbohydrate vaccine or immunotherapeutic (Tn-PS A1) and illustrated to have a robust immune response. Adapting the same approach to investigating the TF antigen (Thomsen Friedenreich antigen, α-D-Gal-(1,3)-β-D-GalNAc), TF was conjugated to another ZPS PS B. The novel TF-PS B conjugate was immunized in Jax C57BL/6 mice to produce both IgG and IgM antibody responses specific for the TF antigen. The study was concluded by showing enhanced binding to the TF-containing MCF-7 breast cancer cell line by fluorescence activated cell sorting (FACS). Additionally, TF-PS A1 elicited similar augmented immune responses to the TF antigen, which enabled in vitro cytotoxicity of tumor cells. In comparison to Tn-PS A1, both the TF-PS B and TF-PS A1 immunogens generated substantial decreased IgG antibody production, which is a main component of the mechanism for tumor elimination. However, an innovative strategy was used to increase the IgG immune responses to the TF antigen through the design and synthesis of a novel bivalent PS A1 construct design capitalizing on the knowledge gained through experimentation with first generation constructs. The importance of cancer vaccine design and development was demonstrated through an immunological investigation of monovalent Tn- and TF-PS A1 constructs leading to a novel, unimolecular Tn-TF-PS A1 bivalent immunogen which significantly increased immunogenicity of the TF antigen (recall: TF-PS A1 did not render a high antibody titer response in mice). This additive “Tn adjuvanting effect” was also iv demonstrated to generate enhanced IgG binding to tumor cell lines MCF-7 and OVCAR- 5 in FACS analysis and in a complement dependent cytotoxicity (CDC) assay monitoring lactate dehydrogenase (LDH) release from noted tumor cells. The results from the CDC assay demonstrated increased tumor cell lysis from Tn-TF-PS A1 sera compared to sera from monovalent vaccines Tn-PS A1 and TF-PS A1. Furthermore, a macrophage galactose lectin 2 (MGL2) assay was used, in conjunction with designed biotinylated probes, to study binding interactions of Tn and TF conjugated to PS A1 vaccine constructs. Our observations concluded that, in the case of the TF antigen, when a unimolecular bivalent Tn-TF-PS A1 immunogen was used, immunogenicity of the TF antigen was increased 50 times over a monovalent TF-PS A1 construct and resulted in a more potent and selective immune response. This work not only validated a MGL2 targeted vaccine design but the premise of which would influence other peptide, protein, or lipid vaccine designs by incorporating Tn antigen. To prove the utility of unimolecular bivalent immunogens, this model was adapted to Globo H-PS A1 construct consisting of Globo H and Tn. Similar to the biological results of Tn-TF-PS A1, the Tn- Globo H-PS A1 immunogen produced a robust IgG immune response with cytotoxicity towards both MCF-7 and HCT-116 cancer cells. In expanding the scope of our work, antibodies have emerged as promising cancer immunotherapies by binding specifically to tumor cells. The generation of the Tn-TF-PS A1, TF-PS A1, and TF-PS B constructs represents entirely carbohydrate moieties that can assist in both tumor binding and killing. Therefore, the generation of monoclonal antibodies (mAb) from these constructs can provide entirely carbohydrate recognition without the influence from peptides or proteins. To this end and to validate our v hypothesis, a IgM mAb was produced that demonstrated selective binding of the Tn antigen and showed potent in vitro and in vivo activity against the MCF-7 tumor cell line. IgM antibodies have often demonstrated recognition of carbohydrate antigens greater than their IgG counterparts through higher avidity. Since, TACAs are present on almost all cancers, having an immunotherapy that can recognize specific glycosides may prove to be an efficient strategy against cancer. More importantly, IgM antibodies have been shown to be effective at mediating complement directed killing of tumor cells. This approach potentially offers a clinical therapeutic benefit. vi I would like to dedicate this dissertation to my wife Ashley, may our lives be filled with happiness and love. I am grateful for all of your support and patience during the course of my academic desires. Acknowledgements I would like to thank Dr. Peter Andreana for all of his support and guidance over the course of my Ph.D. I also owe an immense amount of gratitude to my brother, Dr. Chris Trabbic for inspiring and encouraging me to pursue a career in science. To my lab mates, thank you for your assistance and hours of intense thought provoking debate. v Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ..............................................................................................................v Table of Contents ............................................................................................................... vi List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii List of Schemes ..................................................................................................................xv List of Abbreviations ....................................................................................................... xvi 1 Introduction to Carbohydrate-Based Immunology ..................................................1 1.1. Historical Perspective of Immunity and Vaccines ............................................1 1.2. Vaccine Immunology: Innate and Adaptive Immunity ....................................5 1.3. Biological Significance of Zwitterionic Polysaccharides ...............................12 1.4. Tumor Associated Carbohydrate Antigens (TACAs) .....................................20 1.5. Carbohydrate-Based Cancer Vaccines ............................................................25 1.6. Structural Insights of Tn-PS A1 and Biological activity of Tn-PS A1 ...........32 1.6.1. Conclusions ......................................................................................39 1.6.2. Experimental ....................................................................................39 1.6.2.1. Bacterial Growth and Isolation .........................................39 1.6.2.2. Purification of PS A1 ........................................................41 1.6.2.3. Circular Dichroism............................................................43 vi 1.7. References .......................................................................................................44 2 Immunological evaluation of the entirely carbohydrate-based .................................
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