Engineered human lgG1 for delivery of IDDM self-epitopes

DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus is an autoimmune disease characterized by T cell attack of pancreatic islet cells leading to irreversible loss of the insulin secreting cells. One potential strategy for combatting the autoimmune process involves the initiation of tolerigenic processes that act to tone down or turn off the ongoing cell destruction. A number of T cell self-epitopes have been identified that correlate with the autoimmune process, and this has led to both a better understanding of the genetic component of Type 1 diabetes (T1DM) as well as the attempt to use these self-epitope peptides to specifically target the attacking T cells. To date, the use of the epitope peptide strategy for tolerization has been disappointing due in large part to the problem of delivering the epitope peptides efficaciously. Alliance Pharmaceutical Corp through its susidiary Astral Inc., and colleagues have developed a method for delivering specific epitope peptides to APC through the use of engineered IgG molecules. This strategy has been shown to be highly efficacious in murine autoimmune model systems, most notably the EAE multiple sclerosis model and the NOD mouse model. In recent work it has been shown that 70% of NOD mice on the verge of full blown diabetes can be rescued to normal glycemia using this epitope delivery strategy. We believe that that the bulk of the animal model data generated to date strongly support the transitioning of this technology to human therapeutics. Toward the goal of testing this strategy in human patients an engineered hlgG1 (IgGIN) has been produced. IgGIN carries two Type 1 diabetes-related epitopes: GAD271-285 and insulin9-23. The specific aims of this grant proposal target the initial physical and immunological characterization of IgGIN. Phase 2 of this project will involve scaled-up production of clinical grade IgGIN for toxicology and Phase 1 clinical testing .