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Preclinical Studies of PG70 LEAPS Peptide Vaccines for Rheumatoid Arthritis

PG70 LEAPS 类风湿关节炎肽疫苗的临床前研究

基本信息

批准号：
8777753
负责人：
Daniel Hill Zimmerman
金额：
$ 22.5万
依托单位：
CEL-SCI CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777753
关键词：
Address Adverse effects Affect Aging Animal Model Animals Antibodies Antibody Formation Antigen Presentation Antigens Arthritis Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding Biological Biological Response Modifier Therapy CD4 Antigens CD4 Positive T Lymphocytes Cartilage Cells Clinical Collagen Collagen Arthritis Communicable Diseases Dendritic Cells Deterioration Disease Epitopes Equilibrium Exhibits Female Goals Gold HLA-DR Antigens Health Herpesvirus 1 Histopathology Human Immune Immune response Immunization Immunosuppression In Vitro Inbred BALB C Mice Infection Inflammation Inflammatory Influenza Influenza A Virus, H1N1 Subtype Interleukin-17 J-Chain Immunoglobulins Joints Licensing Ligand Binding Ligands Link MHC Class II Genes Measures Mediating Modeling Molecular Morbidity - disease rate Mus Myocarditis Pain management Pathogenesis Patients Peptide Vaccines Peptides Peripheral Pharmacologic Substance Phase Phenotype Population Production Proteoglycan Recombinants Regulatory T-Lymphocyte Reporting Rheumatoid Arthritis Route Serum Severity of illness Small Business Innovation Research Grant Symptoms System T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Technology Tertiary Protein Structure Testing Therapeutic Intervention Toxic effect Transgenic Organisms Treatment Efficacy Tumor Necrosis Factor-alpha Vaccines Wild Type Mouse base cytokine design efficacy testing in vitro testing in vivo indexing inhibitor/antagonist intraperitoneal joint destruction mouse model novel strategies peptide I preclinical study prevent research study response subcutaneous success

项目摘要

DESCRIPTION (provided by applicant): Currently, FDA-licensed pharmaceuticals used to treat rheumatoid arthritis (RA) focus largely on alleviation of symptoms, either through pain management, general immunosuppression, or by antagonizing cytokines such as TNF-α. Despite recent advances in biologic therapies, these treatments do not address the underlying autoimmune condition. Ligand epitope antigen presentation system (L.E.A.P.S.") conjugates are a peptide vaccine platform designed to modulate the immune response in an antigen-specific manner. LEAPS are composed of two peptide components, an immune cell binding ligand (ICBL) and a peptide (epitope) implicated in an infectious or autoimmune disease. The ICBLs include peptide J from human ß-2 microglobulin, with Th1-polarizing activity, and peptide derG (or G) from human MHC class II ß chain with Th2 polarizing activity. In mice with collagen-induced arthritis (CIA), a Th17-mediated disease, a J-collagen peptide conjugate reduced disease severity by suppressing pro-inflammatory cytokines and increasing protective cytokines. To date, no derG conjugates have shown protective activity. In the present proposal, we hypothesize that L.E.A.P.S. vaccine modulates the immune response towards a protective condition in a second mouse model of RA, cartilage proteoglycan (PG) induced arthritis (PGIA). An advantage of the PGIA model is that it is either a Th1 or Th17 cytokine dependent arthritis based on the route of induction, intraperitoneal (i.p.) or subcutaneous (s.c.), respectively. Using the dominant arthritogenic epitope PG70 (ATEGRVRVNSAYQDK) of the G1 domain of PG, conjugated to J or derG, preliminary studies in the i.p. PGIA model demonstrate that the derG-PG70 conjugate inhibits ongoing arthritis by shifting the balance from a Th1 to a Th2/Treg response. Based on studies in CIA, we expect that the J-PG70 conjugate will modulate pathogenic Th17 responses in s.c.-induced PGIA toward protective Th1 responses. Efficacy will be assessed by measuring arthritis index, histopathological examination of peripheral joints, antibody production, T cell proliferation, and cytokine responses. In Aim 1, we will compare the LEAPS-PG70 peptide conjugates and subunit peptides for therapeutic efficacy in both the i.p. and s.c. PGIA models. In Aim 2, we will examine the mechanism of action focusing on binding to (and effects on) T cells and dendritic cells for the two conjugates using cells from naive PG-TCR-transgenic and PG-immunized (i.p. or s.c.) wild type mice. After success in phase I SBIR, we will advance the L.E.A.P.S vaccine to a phase II SBIR, with the initial goal of further characterizing the mechanisms by which LEAPS peptides act on immune cells from mice and humans, and with the ultimate goal of optimizing the vaccine for the treatment of RA.

描述（由申请人提供）：目前，FDA 许可的用于治疗类风湿性关节炎 (RA) 的药物主要侧重于通过疼痛管理、一般免疫抑制或拮抗细胞因子（如 TNF-α）来缓解症状。尽管生物疗法最近取得了进展，但这些疗法并不能解决潜在的自身免疫性疾病。配体表位抗原呈递系统 (L.E.A.P.S.") 缀合物是一种肽疫苗平台，旨在以抗原特异性方式调节免疫反应。LEAPS 由两种肽成分组成，即免疫细胞结合配体 (ICBL) 和与感染性或自身免疫性疾病有关的肽（表位）。ICBL 包括来自人类的肽 J β-2 微球蛋白，具有 Th1 极化活性，以及来自人 MHC II 类 β 链的肽 derG（或 G），具有 Th2 极化活性。在患有胶原诱导性关节炎 (CIA)（一种 Th17 介导的疾病）的小鼠中，J-胶原蛋白肽缀合物通过抑制促炎细胞因子和增加保护性细胞因子来减轻疾病的严重程度。迄今为止，没有 derG 缀合物已显示出保护活性。在本提案中，我们假设 L.E.A.P.S.在第二种 RA 小鼠模型（软骨蛋白多糖 (PG) 诱导性关节炎 (PGIA)）中，疫苗可调节免疫反应，使其达到保护性状态。 PGIA 模型的一个优点是，根据诱导途径，它是 Th1 或 Th17 细胞因子依赖性关节炎，分别为腹膜内 (i.p.) 或皮下 (s.c.)。使用 PG G1 结构域的显性关节炎表位 PG70 (ATEGRVRVNSAYQDK)，与 J 或 derG 缀合，腹腔内初步研究。 PGIA 模型证明 derG-PG70 缀合物通过将平衡从 Th1 反应转变为 Th2/Treg 反应来抑制正在进行的关节炎。根据 CIA 的研究，我们预计 J-PG70 缀合物将调节皮下诱导的 PGIA 中的致病性 Th17 反应，使其转向保护性 Th1 反应。通过测量关节炎指数、外周关节的组织病理学检查、抗体产生、T细胞增殖和细胞因子反应来评估疗效。在目标 1 中，我们将比较 LEAPS-PG70 肽缀合物和亚基肽在腹腔注射和腹腔注射中的治疗效果。和 s.c. PGIA 型号。在目标 2 中，我们将使用来自初始 PG-TCR 转基因小鼠和 PG 免疫（腹膜内或皮下）野生型小鼠的细胞，研究两种缀合物的作用机制，重点是与 T 细胞和树突状细胞的结合（以及对 T 细胞和树突状细胞的影响）。在 I 期 SBIR 取得成功后，我们将把 L.E.A.P.S 疫苗推进到 II 期 SBIR，初步目标是进一步表征 LEAPS 肽作用于小鼠和人类免疫细胞的机制，最终目标是优化治疗 RA 的疫苗。