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Novel Antigen-Specific Immunomodulatory Tregitope-based Therapy to Address Autoimmune Pathogenesis in Graves' Disease

基于新型抗原特异性免疫调节 Tregitope 的疗法可解决格雷夫斯病的自身免疫发病机制

基本信息

批准号：
9410057
负责人：
Anne Searls DeGroot
金额：
$ 17.7万
依托单位：
EPIVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9410057
关键词：
Ablation Address Adverse effects Animal Model Antibodies Antibody Response Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Binding Biological Assay Biological Response Modifier Therapy Bystander Suppression CD4 Antigens CD4 Positive T Lymphocytes Cells Chemicals Child Clinical Clinical Treatment Code Disease Down-Regulation Effector Cell Electroporation Epitopes Eragrostis Evaluation Excision Extracellular Domain Eye diseases FDA approved Formulation Future Gland Glycolates Graves&apos Disease HLA-DR3 Antigen Half-Life Homeostasis Human Hyperthyroidism Hypothyroidism Immune Immune Tolerance Immune response Immunity Immunize Immunoglobulin G Life Link Lymphocyte MHC Class II Genes Mediating Methods Microspheres Modeling Monitor Mus Muscle Operative Surgical Procedures Pathogenesis Patients Peptide Hormones Receptors Peptides Peripheral Peripheral Blood Mononuclear Cell Phase Plasmids Pregnant Women Production Property Radioactive Iodine Recombinants Regulatory T-Lymphocyte Replacement Therapy Research Serum Serum Albumin Splenocyte System T cell response T-Lymphocyte Testing Tetanus Toxoid Thyroid Gland Thyroid Hormones Thyroid stimulating immunoglobulins Thyrotropin Receptor Toxic effect base clinical application extracellular immunoregulation improved in vivo mouse model novel product development receptor binding response

项目摘要

ABSTRACT Significance: Graves’ disease (GD), one of the most prevalent autoimmune diseases, is caused by stimulating autoantibodies (TSAb) to the Thyroid-Stimulating Hormone Receptor (TSHR), resulting in hyperthyroidism. Current methods for managing hyperthyroidism in GD target excess thyroid hormone secretion by ablation or removal of the thyroid or by blocking thyroid hormone synthesis. Each of these therapies is associated with adverse effects, most commonly hypothyroidism requiring life-long replacement therapy. Importantly, none of these approaches address the underlying anti-TSHR CD4 T cell response that contributes to the continued production of TSAb auto-antibodies. Autoimmunity is the result of an imbalance in Teffector:Tregulatory (Teff:Treg) immune-cell homeostasis, and a loss of central or peripheral immune tolerance. T regulatory epitopes (Tregitopes) found in IgG stimulate proliferation and activation of natural and induced Tregs, thereby downregulating a Teff response to self-antigens. These Tregitopes when administered with MHC Class II binding self-antigen peptides, will elicit Antigen- Specific Adaptive Tolerance Induction (ASATI). Hypothesis: Tregitopes, in combination with the target antigen —TSHR CD4 T cell effector peptides — will reduce CD4 T cell activation and T-dependent B cell production of TSAb. Due to the short half-life of peptides in vivo, a practical Tregitope BioTherapeutic (Treg-BT) will need to be administered in a suitable delivery system, that improves its PK/PD properties with minimal toxicity. This project will identify TSHR peptides that stimulate a CD4 effector immune response in PBMC from GD patients, and combine the optimal peptide(s) with Tregitopes in an effective delivery vehicle. In Specific Aim 1, TSHR peptides identified to stimulate a CD4 effector cell response in GD patients will be tested for inhibition by Tregitopes in a TSHR bystander suppression assay. Tregitope peptides with and without TSHR peptides will then be formulated into two Treg-BT delivery vehicles: a) chemically ligated to a recombinant FDA-approved human serum albumin (HSA) or b) formulated into poly(lactic-glycolic acid) (PLGA) microspheres. The Treg-BT will then be tested in the TSHR bystander suppression assay with PBMC from GD patients. In Specific Aim 2, the candidate Treg-BT (HSA- Tregitope + TSHR peptide or Tregitope + TSHR peptides in microspheres, with appropriate controls) will be tested in vivo in a mouse model of GD. HLA-DR3 mice will be genetically immunized with an expression plasmid coding for the extracellular domain of TSHR to generate TSAb. After TSAb response is established, the mice will be treated with the optimized Treg-BT and serum TSAb and CD4 T cell responses will be monitored. Overall Impact: These studies will produce candidate Treg-BT which, combined with TSHR peptides, stimulate a Treg-mediated down-regulation of TSAb autoantibodies, with potential fast-track applicability to the treatment of patients with clinical Graves’ disease.

摘要