IM Therapeutics is developing personalized immuno-therapeutic drugs for autoimmune diseases based on the genetic risk attributed by human leukocyte antigen (HLA) genes. Our lead candidate drug is an oral drug that starves the autoimmune process in type 1 diabetes (T1D) by blocking DQ8 on specific immune cells. Our goal is to preserve pancreatic beta cell function and maintain normal insulin production in at-risk and early-stage patients with type 1 diabetes. We are leveraging our HLA platform to expand our pipeline beyond T1D, to include drug development for Celiac disease (gluten sensitivity) as well as potential additional autoimmune diseases.
Autoimmune disease is promoted when the immune system becomes “intolerant” of self-tissues such that it attacks specific cells of the respective disease, for example, the insulin-producing cells of the pancreas in Type 1 Diabetes (T1D) or the small intestine in Celiac disease.
The antigen-presenting cells (APCs) of the immune system (e.g., B cells, dendritic cells, macrophages) normally maintain immune tolerance by presenting specific parts of self-tissues, termed self-antigens (autoantigens), on their surface to harmful autoreactive immune cells to induce their death or to generate protective immune cells.
These APCs do not simply place autoantigens anywhere on their surface, but rather use special “platter” molecules, termed Human Leukocyte Antigen (HLA), to make the autoantigen recognizable (palatable) to such harmful or protective immune cells. However, because HLA molecules arise from genes that are slightly different among individuals (i.e.,alleles), so-me HLA alleles function in an abnormal way to “mis-present” self-antigens that leads to autoimmune diseases. The HLA-DQ8 and DQ2 genes are known to predispose risk for both T1D and Celiac disease. HLA-DQ8 occurs in 50 – 60% of all T1D patients and in 10% of Celiac disease patients and is easily identified by established genetic screening techniques. Nearly 100% of Celiac patients have DQ2 and/or DQ8. In fact, many HLA genes confer significant risk for specific autoimmune diseases (table).
Our platform uses a supercomputer to screen millions of ‘drug-like’ compounds to interact with a given HLA molecule. Top scoring ‘hits’ are then evaluated with in vitro assays and subsequent in vivo testing. Lead candidates are further optimized for blocking a specific HLA molecule and developed for clinical use. With this platform in place, it is possible to develop a pipeline of drugs for each HLA molecule that confers risk for developing a given autoimmune disease in the above table.
Advantages of our approach:
- Targets the root cause of autoimmunity with an oral small molecule drug design
- Developed to minimize interference with other normal immune responses such as infections
- Extensible platform to identify drugs for multiple HLA-associated autoimmune indication
INSULIN IS NOT A CURE
While insulin injections or infusion allow a person with T1D to stay alive, they do not cure the disease, nor do they necessarily prevent the possibility of the disease’s serious effects, which may include: kidney failure, blindness, nerve damage, heart attack, stroke, and pregnancy complications.1
Type 1 Diabetes
Type 1 diabetes (T1D) is the immune mediated form of diabetes that results from the body’s destruction of insulin producing pancreatic beta-cells. Immune cells, particularly T and B cells, contribute to the killing of insulin producing beta-cells. A lack of sufficient insulin production results, which prevents tissues from using glucose, leading to high blood sugars. Treatment is with life-long insulin administration by an insulin pump or multiple daily injections. Genetic risk for T1D development is predisposed by the HLA-DQ8 gene. People with this gene are ~11x more likely to develop T1D than those that do not have the gene, and 50-60% of all patients with T1D have the HLA-DQ8 gene.
IMT’s approach to T1D is to develop a small molecule drug that effectively starves the autoimmune process by blocking the function of DQ8 bearing cells to activate T-lymphocytes. Our lead drug, IMT-002, occupies this peptide binding groove of DQ8 on the surface of antigen presenting cells to block the binding of insulin and other beta-cell proteins and subsequent activation of CD4 T-cells. When HLA-DQ8 is blocked, the immune system will no longer attack insulin producing beta-cells, thus modifies the disease course to keep patients making their own insulin.
3M Americans are living with celiac disease
With no approved therapies, the only current treatment for people living with celiac is a gluten-free diet.
Celiac disease (gluten sensitivity) is an autoimmune disease that results when the body’s immune system attacks the small intestine when exposed to gluten. HLA-DQ2 predisposes a strong risk for developing Celiac disease, and ~90% of patients have the HLA-DQ2 gene while the remaining 10% have DQ8. The only treatment for Celiac disease is a life-long avoidance of foods that contain gluten.
IMT’s approach to Celiac disease is to identify and develop an oral small molecule drug that blocks the function of HLA-DQ2, the major genetic risk factor for Celiac disease. Our platform approach has identified candidate drugs that specifically block DQ2, and these lead compounds are undergoing further development and testing prior to use in patients.
Ostrov DA, Alkanani A, McDaniel KA, Case S, Baschal EE, Pyle L, Ellis S, Pöllinger B, Seidl KJ, Shah VN, Garg SK, Atkinson MA, Gottlieb PA, Michels AW. Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes . J Clin Invest 2018 Feb; 128(5):1888-1902
Michels AW, Gottlieb PA. Learning From Past Failures of Oral Insulin Trials. Diabetes
Atkinson MA, Eisenbarth GS, Michels AW. Type 1 Diabetes. Lancet 2014; 383: 69-82
Simmons KM, Gottlieb PA, Michels AW. Immune Intervention and Preservation of Pancreatic Beta Cell Function in Type 1 Diabetes. Current Diabetes Reports 2016 Oct; 16(10):97 (subscription required)
Michels AW, Ostrov DA, Zhang L, Nakayama M, Fuse M, McDaniel K, Roep BO, Gottlieb PA, Atkinson MA, Eisenbart GS. Structure-based selection of small molecules to alter allelespecific MHC class II antigen presentation J Immunol. 2011 December 1; 187(11): 5921-5930
Gough SCL, Simmonds MJ. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Current Genomics 2007 Nov; 8(7): 453-465