Objective
The objective of this proposal is to determine the efficacy and safety of novel combination therapy using long-acting mIL-2/CD25 fusion protein (mIL-2/CD25) and Bruton’s tyrosine kinase (BTK) inhibitor in the preclinical NOD mouse model. This is supported by our preliminary data and the literature suggesting that both T and B cell pathways are critical in the initiation and pathogenesis of T1D; 1) we demonstrated that mIL-2/CD25 fusion protein prevents the onset of diabetes in NOD mice, and 2) B cell depletion or blocking the pathogenic function of BTK reduces diabetes in the NOD mice and autoimmunity in other models.
Background Rationale
Type 1 diabetes (T1D) afflicts more than 1.4 million people in the U.S. including 500,000 children and the incidence is increasing (JDRF, CDC). Currently, exogenous insulin is used to manage diabetes. Yet, insulin insufficiency and hypoglycemia severely affect many metabolic activities in the body with severe consequences on body weight and susceptibility to a wide variety of diseases. Because T1D results from the destruction of the pancreatic beta-cells by an autoimmune process, therefore, therapies that can reduce or block the autoimmune attack rather than supplementing insulin are highly desirable. Consistently, T and B lymphocytes of the adaptive immune system have been identified as therapeutic targets for T1D, but the current forms of therapy cause severe immunodeficiency and increased susceptibility to infections and cancer. We have developed a highly effective and long-acting analog of cytokine IL-2 that increases the number and competence of regulatory T cells which are a physiological suppressor of diabetogenic T cells. Ibrutinib is an approved drug that inhibits B lymphocytes that facilitate pathogenic T cell destruction of the pancreatic beta-cells. Therefore, we propose to use a therapy combining the two efficacious drugs (mIL-2/CD25 and Ibrutinib) to treat and reverse T1D. This combination therapy is expected to simultaneously suppress diabetogenic T cells and prevent their continued activation by B lymphocytes for prolonged relief from the immune destruction of beta-cells and preserve pancreatic function without causing severe immunodeficiency. Because the two drugs are already in use in human, this strategy should bring the benefits of our combination therapy rapidly to the patients.
Description of Project
Type 1 diabetes (T1D), previously known as juvenile diabetes is one of the most common chronic diseases in which pancreatic beta-cells that produce insulin are destroyed by the immune system resulting in insulin deficiency. The resulting increased blood sugar (hyperglycemia) leads to several metabolic disorders and is a leading cause of blindness, amputation, and kidney failure. T1D affects more than 1.4 million people in the U.S. including 500,000 children, and its incidence is increasing. Although the causes remain unclear, it is well established that T1D results from an autoimmune process that specifically attacks the pancreatic beta-cells.
Two types of immune cells called B lymphocytes and regulatory T cells (Treg) play a crucial role in this process and can be considered T1D accelerator and the brake, respectively. Indeed, while the B lymphocytes enhance the autoimmune disease, the Tregs try to restrain it. Thus, the best way to stop the disease is to (dampen the autoimmune activation and bolster autoimmune suppression) release the gas pedal and push on the brake.
Dr. Khan (contact PI and B cell expert) pioneered the work on BTK function in B cells and now repurposing a commercial BTK inhibitor drug called Ibrutinib in autoimmune diseases. Ibrutinib blocks B cell activity and restrain autoimmunity in various mouse models and it is currently in many clinical trials for autoimmune diseases. Concurrently, Dr. Malek (co-PI and Treg expert) developed a new drug called mIL-2/CD25 fusion protein that expands Treg number and limits diabetes progression in animal models. This new drug underwent preclinical development, showed an excellent safety profile, and is being tested in human.
We propose the use of these two drugs in combination to restrain B lymphocyte activity and increase Treg number and function. We hypothesize that this combinatorial treatment will be safe and more powerful than either single therapy in blocking the immune attack and restraining diabetes progression. In particular, we wil first assess the safety and the therapeutic effects of the proposed drug combination and compare it with those of single drugs. We will study how this combination therapy affects hyperglycemia, insulin-producing cells and immune cells and explore the molecular pathways in T and B cells that are modulated by the drugs.
In summary, we expect that our strategy will be able to stop or significantly delay T1D progression because of the crucial but opposite roles of B lymphocytes and Treg cells in this autoimmune disease. Given the excellent safety profile of IL2-CD25 recombinant protein and BTK inhibitor ibrutinib, we expect the combinatorial therapy to be safe. If our hypothesis is true, we envision a rapid translation of this strategy in the clinic since ibrutinib is already used in humans and because IL2-CD25 protein is being evaluated in clinical trials.
Anticipated Outcome
Preclinical assessment of our combination therapy suppressing diabetogenic T cells and the B cells that conspire with them will facilitate the rapid clinical translation of a novel combination immunotherapy for type 1 diabetes.
Relevance to T1D
In Type-1 diabetes (T1D) the pancreatic beta-cells in the pancreatic islets are destroyed by highly specific autoimmune attack. This specific nature of the immune response against a self-tissue suggests a critical role for T and B cells of the immune system. Normally, these are the immune cells that provide exquisitely specific protective immunity against millions of microbes. Therefore, these two cell types are therefore the key to the autoimmune attack on the pancreatic beta-cells and can be used for targeted immunotherapy. Therefore, identifying and evaluating means to manipulate the autoimmune process is highly relevant for developing therapies for T1D. We have developed a drug candidate to suppress diabetogenic T cells (mIL-2/CD25) and have identified another drug to dampen the B cells’ ability to continuously support the diabetogenic T cells. This drug combination is designed suppress the autoreactive immune cells while sparing the overall functionality of the immune system.