Synthesis and Characterization of Antigen-Containing Bioconjugates Used to Probe and Modulate Autoimmunity

Abstract

Autoimmune diseases afflict a significant part of the world population and current treatments only treat symptoms or delay the progression of the disease. In the first chapter of this dissertation, an introduction into autoimmunity and current clinically available non-antigen-specific treatments was presented, along with an overview of the rise of antigen-specific immunotherapies (ASIT) as an improved strategy for the treatment of autoimmune diseases. Furthermore, a detailed background into the chemistry utilized in this work to construct novel antigen-specific probes as potential therapies for autoimmune disorders was also offered. A novel class of bioconjugates known as antigen-drug conjugates (AgDCs) have been developed in our group. AgDCs utilize a similar directing strategy as antibody-drug conjugates (ADCs), which use a protein or peptide autoantigen (vehicle) to direct a conjugated drug (payload) to antigen-specific immune cells. Thus, AgDCs are a novel ASIT that may be used to treat autoimmune disorders. Chapter 2 is focused on the synthesis of various chemical biology tools, and the synthetic optimization of ‘clicking’ a modified-mimotope or a synthetic epitope to a potent drug via copper-catalyzed cycloaddition (CuAAC). This work also explored another potential novel therapeutic known as Soluble Antigen Arrays (SAgAs) developed in our group. SAgAs are constructed by using a hydrophilic linear polymer, hyaluronic acid (HA), grafted with multiple repeating autoantigen. SAgA technology introduced tolerance and suppressed disease in several studies in the mouse model of Multiple Sclerosis. SAgAs were also designed for flexibility in accommodating other autoantigens and for facilitating screening of antigen valency effects. Two new type of SAgAs were constructed and characterized using different Type 1 Diabetes autoantigens, namely p79 (chapter 3) and human insulin (chapter 4). Both cSAgAp79 and SAgAIns were tested in vitro to determine if the SAgAs are able to modulate immunological systems.