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（由适用提供）：目前，用于治疗类风湿关节炎（RA）的FDA许可的药物很集中在减轻症状，通过疼痛管理，一般的免疫抑制或拮抗TNF-α等细胞因子。尽管生物疗法最近取得了进步，但这些疗法并未解决潜在的自身免疫性疾病。 Ligand epitope antigen presentation system (L.E.A.P.S.") Conjugates are a peptide vaccine platform designed to modulate the immunoresponse in an antigen-specific manner. LEAPS are composed of two peptide components, an immunocell binding ligand (ICBL) and a peptide (epitope) implemented in an infectious or autoimmune disease. The ICBLs include peptide J from human ß-2 microglobulin, with Th1-pollarizing 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 protected cytokines. To日期，在目前的提案中，没有Derg偶联的活性。诱导，腹膜内（i.p.）或皮下（S.C.） PG的G1结构域的主要关节炎表位PG70（Ategrvrvnsayqdk）与J或Derg结合，在I.P.中进行了初步研究。 PGIA模型表明，Derg-PG70结合物通过将平衡从TH1转移到Th2/Treg响应来抑制持续的关节炎。根据CIA的研究，我们预计J-PG70结合物将调节S.C.诱导的PGIA对保护性Th1反应的致病性TH17反应。将通过测量关节炎指数，周围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效果。在AIM 1中，我们将比较i.p.中的LAKEP-PG70肽结合物和亚基肽的治疗效果。和S.C. PGIA模型。在AIM 2中，我们将使用来自幼稚的PG-TCR- TCR-转基因和PG免疫（I.P.或S.C.或S.C.）野生型小鼠的细胞来研究两种结合物的作用机理。在第一阶段SBIR中取得成功之后，我们将将L.E.A.P.S疫苗推向II期SBIR，其最初的目标是进一步表征Pepperides在小鼠和人类的免疫细胞上起作用的机制，并以优化RA治疗疫苗的最终目标。