| dc.description.abstract | Lipid 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 |
