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Novel toll-like receptor 4 ligands: synthesis, biological studies and applications in molecular vaccines

dc.contributor.advisorUlanova, Marina
dc.contributor.advisorJiang, Zi-hua Justin
dc.contributor.authorLewicky, Jordan David
dc.description.abstractLipid A, a unique disaccharide glycolipid, is the active principle of Gram-negative bacterial lipopolysaccharide in activating the innate immune response via Toll-like receptor 4 (TLR4). Given the important role that TLR4 plays in innate immunity, and ultimately, the development of an adaptive immune response, ligands that can modulate TLR4-mediated signalling have great therapeutic potential as both vaccine adjuvants, and anti-sepsis agents. In attempting to develop novel ligands which can successfully modulate TLR4-mediated signalling in a well defined fashion, simplified structures which aim to mimic the natural lipid A structure have shown great promise. The notion of cancer immunotherapy, in which the vast power of the immune system is tapped to prevent and/or eradicate the disease has begun to garner considerable attention. Tumour associated carbohydrate antigens, carbohydrate containing epitopes which are either unique of over-expressed by cancer cells, are viable targets of said immunotherapy. A major limitation, however, is the low antigenicity displayed by these carbohydrate epitopes. Studies have shown that the inclusion of adjuvant structures, especially when directly chemically conjugated to the antigen, improve the success of anti-cancer vaccination efforts. The primary goal of this study has been aimed at the development of novel vaccine adjuvants, specifically the design of novel molecular frameworks to mimic the structure of lipid A in the activation of TLR4. A secondary goal of this study has aimed at the application of successful novel lipid A mimics as the immunostimulatory component of self-adjuvanting carbohydrate antigens for use in therapeutic cancer vaccines. One novel molecular framework that has been designed and synthesized employs a flexible, acyclic diethanolamine-based scaffold to mimic one of the sugar moieties natural to the lipid A disaccharide. Several structural variations of this framework were generated for structure-activity relationship studies in an effort to maximize immunostimulatory potency. The mimics were evaluated in vitro for their ability to induce TLR4-mediated cytokines. All variations showed confirmed TLR4 stimulatory activity, the potency of which was dependent on the functionalization of the terminal ethanol moiety of the diethanolamine-based acyclic scaffold. In vivo studies evaluating the adjuvant potential of this novel family of lipid A mimics are currently underway. As part of an industrial partnership aimed at the development of novel vaccine adjuvants, a second lipid A mimic framework was designed and synthesized, in which an aromatic residue has been incorporated into the structural backbone. Two structural variations of the framework were generated which vary in the functionalization of the phenolic hydroxyl of the aromatic-based backbone. Several in vivo studies have shown that both mimics exhibit potent TLR4 immunostimulatory activity, and successful adjuvant properties. In an effort to construct a fully synthetic, self-adjuvanting tumour associated carbohydrate antigen for eventual use in therapeutic cancer vaccines, the immunostimulatory activity of the diethanolamine-based lipid A mimic framework designed herein, was tapped. As such, a conjugate structure in which the lipid A mimic framework and the Thomsen-Friedenreich carbohydrate antigen are directly linked via a flexible chemical linker was designed and synthesized. Future studies will determine the ability of the conjugate to induce an effective antibody response towards the carbohydrate epitope.en_US
dc.subjectImmune systemen_US
dc.subjectToll-like receptorsen_US
dc.subjectToll-like receptor 4en_US
dc.subjectCancer immunotherapyen_US
dc.subjectDiethanolamine-containing lipid A mimicsen_US
dc.subjectImproving immunostimulatory potencyen_US
dc.subjectAromatic-based lipid A mimicsen_US
dc.titleNovel toll-like receptor 4 ligands: synthesis, biological studies and applications in molecular vaccinesen_US
dc.typeDissertationen_US Universityen_US

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