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.
Public Health Relevance: 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.
Thesaurus Terms: Atgn;Adverse Effects;Affect;Age;American;Animal Model;Animal Models And Related Studies;Antibodies;Antigen Presentation;Antigens;Apoptosis;Apoptosis Pathway;Atrophic Arthritis;Autoantigens;Autoimmune Diseases;Autoimmune Status;Autoimmune Thyroiditis;Autoimmunity;Autologous Antigens;Autoregulation;B7-1;Bb1;Benefits And Risks;Beta Cell;Bifunctional Antibodies;Binding;Binding (Molecular Function);Bispecific Antibodies;Bispecific Monoclonal Antibodies;Body Tissues;Brittle Diabetes Mellitus;Cd11c;Cd152;Cd152 Antigen;Cd152 Antigen Gene;Cd152 Gene;Cd25;Cd28;Cd28 Gene;Cd28lg;Cd28lg1;Cd80;Cd80 Gene;Ctla 4;Ctla-4 Gene;Ctla-4 Antigen;Ctla4;Ctla4 Protein;Ctla4 Gene;Ctla4-Tm;Cancers;Categories;Cell Surface;Cells;Chronic Lymphocytic Thyroiditis;Clinical;Clinical Evaluation;Clinical Testing;Clinical Treatment Moab;Clinical, Transplantation, Organ;Closure By Ligation;Complex;Cricetinae;Cytotoxic T-Lymphocyte Protein 4;Cytotoxic T-Lymphocyte Protein 4 Gene;Cytotoxic T-Lymphocyte-Associated Antigen 4;Cytotoxic T-Lymphocyte-Associated Antigen 4 Gene;Cytotoxic T-Lymphocyte-Associated Protein 4;Cytotoxic T-Lymphocyte-Associated Serine Esterase-4;Cytotoxic T-Lymphocyte-Associated Serine Esterase-4 Gene;Data;Dendritic Cells;Development;Diabetes Mellitus;Direct Costs;Disease;Disorder;Disseminated Sclerosis;Dose;Down-Regulation;Down-Regulation (Physiology);Downregulation;Drugs;Effector Cell;Eragrostis;Facilities And Administrative Costs;Glut2;Glut2 Gene;Generations;Goals;Graft Material;Grafting Procedure;Hamsters;Hamsters Mammals;Hashimoto Disease;Hashimoto's Disease;Hashimoto's Struma;Hashimoto's Thyroiditis;Hashimoto's Syndrome;Hashimotos Disease;Hepatic Cells;Hepatic Parenchymal Cell;Hepatocyte;Homeostasis;Human;Humulin R;Hybridomas;Hyperglycemia;Iddm;Il2r;Il2ra;Il2ra Gene;Itgax;Itgax Gene;Immune;Immune Response;Immune System;Immunosuppressants;Immunosuppression Effect;Immunosuppressions (Physiology);Immunosuppressive Agents;Immunosuppressive Effect;Inbred Nod Mice;Indirect Costs;Infection;Infectious Agent;Inflammatory Arthritis;Insulin;Insulin (Ox), 8a-L-Threonine-10a-L-Isoleucine-30b-L-Threonine-;Insulin Cell;Insulin Secreting Cell;Insulin-Dependent Diabetes Mellitus;Islet Cell;Juvenile-Onset Diabetes Mellitus;Ketosis-Prone Diabetes Mellitus;Kidney Tubules;Knock-Out Mice;Knockout Mice;Lab7;Lead;Left;Ligation;Liver Cells;Lupus Erythematosus Disseminatus;Lymphocytic Thyroiditis;Lymphomatous Thyroiditis;Mhc Receptor;Ms (Multiple Sclerosis);Major Histocompatibility Complex Receptor;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Marketing;Mature T-Cell;Mature T-Lymphocyte;Mediating;Medication;Mice;Mice Mammals;Modern Man;Molecular Interaction;Monoclonal Antibodies;Multiple Sclerosis;Murine;Mus;Nod Mouse;Natural Immunosuppression;Non Obese;Non-Obese Diabetic Mice;Nonobese;Nonobese Diabetic Mouse;Novolin R;Null Mouse;Opportunistic Infections;Organ Transplantation;Organ Transplants;Organ Transplants, Including Bone Marrow For Dct;Pancreas;Pancreatic;Pathway Interactions;Patients;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Phase 2 Clinical Trials;Phase Ii Clinical Trials;Physiologic Pulse;Physiological Homeostasis;Plague;Play;Population;Preparation;Procedures;Process;Programmed Cell Death;Pulse;Receptors, Antigen, T-Cell;Regular Insulin;Regulatory T-Lymphocyte;Renal Tubule Structure;Rheumatoid Arthritis;Risk;Role;Scid Mice;Sle;Sttr;Scientist;Self-Antigens;Severe Combined Immunodeficient Mice;Signal Pathway;Small Business Technology Transfer Research;Specificity;Staging;Sudden-Onset Diabetes Mellitus;Systemic Lupus Erythematosus;Systemic Lupus Erythmatosus;Systemic Sle - 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