Use of Bispecific Antibody for Treating Non-obese Diabetes

双特异性抗体用于治疗非肥胖型糖尿病的用途

• 批准号: 8056696
• 负责人: Bellur S Prabhakar
• 金额: $ 19.27万
• 依托单位: TOLEROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056696
• 关键词: Adverse effects; Affect; Age; American; Animal Model; Antibodies; Antigen Presentation; Antigens; Apoptosis; Autoantigens; Autoimmune Diseases; Autoimmune thyroiditis; Autoimmunity; Benefits and Risks; Beta Cell; Binding; Bispecific Antibodies; Bispecific Monoclonal Antibodies; CD28 gene; CD80 gene; CTLA4 gene; Categories; Cell surface; Cells; Clinical; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Dendritic Cells; Development; Diabetes Mellitus; Direct Costs; Disease; Dose; Down-Regulation; Effector Cell; Eragrostis; Facilities and Administrative Costs; GLUT2 gene; Generations; Goals; Hamsters; Hashimoto Disease; Hepatocyte; Homeostasis; Human; Hybridomas; Hyperglycemia; IL2RA gene; ITGAX gene; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Inbred NOD Mice; Infection; Infectious Agent; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Knockout Mice; Lead; Left; Ligation; Malignant Neoplasms; Marketing; Mature T-Lymphocyte; Mediating; Monoclonal Antibodies; Multiple Sclerosis; Mus; Non obese; Opportunistic Infections; Organ Transplantation; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiologic pulse; Plague; Play; Population; Preparation; Procedures; Process; Regulatory T-Lymphocyte; Renal tubule structure; Rheumatoid Arthritis; Risk; Role; SCID Mice; Scientist; Signal Pathway; Small Business Technology Transfer Research; Specificity; Staging; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic antibodies; Thyroid Diseases; Thyroid Gland; Time; Tissues; Toxicity Tests; Transplantation; Transplanted tissue; United States; Work; anergy; attenuation; base; cancer risk; clinical application; diabetic; effective therapy; in vivo; inhibitor/antagonist; innovation; mouse model; novel; prevent; protective effect; research clinical testing; research study; response; stability testing

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：成熟T淋巴细胞的激活是一个多步骤的过程，需要ag特异性触发TCR复合物和通过CD28-CD80/CD86途径介导的共刺激。CTLA-4是T细胞活化的关键抑制剂，在CTLA-4敲除小鼠中观察到的致命淋巴细胞增殖证明了这一点。这些信号通路在T细胞稳态中起主要作用，操纵这些通路已成为抑制自身免疫的有效策略，具有临床应用价值。过去，Tolerogenics产生了针对TSHR和CTLA-4特异性的双特异性抗体（BsAb）。BsAb的抗tshr部分可以与表达tshr的甲状腺组织结合，而抗CTLA-4部分则与攻击T细胞上表达的CTLA-4结合。我们的研究结果表明，使用这种BsAb耐受性可以诱导和抑制自身免疫性甲状腺炎。疾病抑制与CD4+CD25+ Treg细胞亚群的选择性扩增有关。这些结果支持了靶向CTLA-4参与可能导致Treg细胞选择性扩增的观点，Treg细胞可以介导对特定自身抗原的持续低反应性。最近，使用抗原脉冲dc包被CD11c（树突状细胞表面标记物）和CTLA-4特异性BsAb对桥本甲状腺炎和1型糖尿病有类似的保护作用。因此，CTLA-4靶向活化T细胞可能是抑制NOD小鼠1型糖尿病模型自身免疫的有效手段。

项目成果

A novel pancreatic β-cell targeting bispecific-antibody (BsAb) can prevent the development of type 1 diabetes in NOD mice.

一种新型的胰腺β细胞靶向双特异性抗体（BSAB）可以防止NOD小鼠中1型糖尿病的发展。

• DOI: 10.1016/j.clim.2014.04.014
• 发表时间: 2014-07
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Bhattacharya P;Fan J;Haddad C;Essani A;Gopisetty A;Elshabrawy HA;Vasu C;Prabhakar BS
• 通讯作者: Prabhakar BS