Activation of mature T lymphocytes is a multi-step process requiring both Ag-specific triggering of the TCR complex and co-stimulation mediated through the CD28-CD80/CD86 pathway. CTLA-4 is a critical inhibitor of T cell activation as evidenced by the lethal lympho-proliferation seen in CTLA-4 knockout mice. These signaling pathways play a primary role in T cell homeostasis and manipulating these pathways has emerged as a powerful strategy to suppress autoimmunity with clinical applications. In the past, Tolerogenics generated bispecific antibodies (BsAb) with specificities for TSHR and CTLA-4. The anti-TSHR portion of the BsAb could bind to the TSHR-expressing thyroid tissue leaving the anti-CTLA-4 portion to engage CTLA-4 expressed on the attacking T cells. Our results showed that using this BsAb tolerance could be induced and autoimmune thyroiditis suppressed. The disease suppression was associated with selective expansion of a subpopulation of CD4+CD25+ Treg cells. These results supported the notion that targeted CTLA-4 engagement could result in a selective expansion of Treg cells that can mediate persistent hyporesponsiveness to specific self antigens. Recently, Similar protective effects against Hashimoto's thyroiditis and type-1 diabetes have been noted using antigen-pulsed DCs coated with a CD11c (a dendritic cell surface marker) and CTLA-4 specific BsAb. Therefore, targeted engagement of CTLA-4 on activated T cells could provide an effective means of suppressing autoimmunity in NOD mouse model of type-1 diabetes. Based on these observations, the Company hypothesizes that """"""""Engagement of CTLA-4 concomitant with Ag-specific T-Cell Receptor (TCR) ligation can be used to down modulate pathogenic self reactive T effector cell (""""""""Teff"""""""") responses, while inducing Tregs that can suppress Teff function as a means of targeted therapy to: i) prevent the development of T1D;and, ii) stabilize or ameliorate ongoing T1D."""""""" To test this hypothesis, Tolerogenics will develop a BsAb that can selectively target mouse beta cells through GLUT2 and down modulate beta cell infiltrating T cells through targeted CTLA-4 engagement in non-obese diabetic (NOD) mice that spontaneously develop type-1 diabetes.
Aim -1. Construction and characterization of BsAb to mouse GLUT2 and CTLA-4.
Aim -2. To test the ability of anti-mouse GLUT2-anti-CTLA-4 BsAb to suppress T1D. Generation of BsAb that can be used to specifically suppress, stabilize or reverse type-1 diabetes will have significant clinical implications for developing novel therapies for type-1 diabetes in humans.
Autoimmune disease is the third major category of illnesses plaguing the United States and the most common of these diseases affect more than 8.5 million Americans. The burden of immune-mediated diseases is staggering. In the US alone, these conditions result in direct and indirect costs that exceed $100 billion. Existing clinical approaches to autoimmune disorders have relied on the administration of immunosuppressive drugs that result in suppressing the entire immune system. Such a response makes a patient susceptible to a wide range of infectious agents. In Tolerogenics'application, the company proposes to test specific therapeutic approaches aimed at restoring immune regulation and down regulating only the aberrant immune responses using a proprietary bispecific antibody for the treatment of Type I Diabetes, initially. This technology could have major importance not only Type I Diabetes treatment efforts, but for a variety of other autoimmune diseases in the United States including systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis, Grave's thyroid disease, Hashimoto's thyroiditis, and others.
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