Preclinical studies of PG70 LEAPS peptide vaccines for rheumatoid arthritis

PG70 LEAPS肽疫苗治疗类风湿性关节炎的临床前研究

基本信息

批准号：
9566859
负责人：
Daniel Hill Zimmerman
金额：
$ 69.15万
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9566859
关键词：
Adoptive Cell Transfers Adoptive Transfer Adult Adverse effects Adverse reactions Affect Aging Animal Model Animals Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Arthritis Autoimmune Diseases Autoimmune Process Autoimmune Responses Autologous B-Lymphocytes Binding Biological Assay Biological Response Modifier Therapy Blood Cells CD4 Positive T Lymphocytes Cartilage Cell Culture Techniques Cell Therapy Cells Characteristics Citrulline Clinic Clinical Dendritic Cells Deterioration Disease Disease Progression Epitopes Female Funding Genetic Gold Helper-Inducer T-Lymphocyte Histopathology Human Immune Immune Targeting Immune response Immune system Immunization Immunize Immunodeficient Mouse Immunodominant Epitopes Immunosuppression Immunotherapy In Vitro Inbred BALB C Mice Infection Inflammation Inflammatory Joints Ligand Binding Ligands MHC Class II Genes Malignant Neoplasms Modeling Molecular Mus Pain management Pathologic Patients Peptide Vaccines Peptide antibodies Peptides Peripheral Pharmaceutical Preparations Pharmacologic Substance Phase Population Production Proteoglycan Rattus Recombinants Regulatory T-Lymphocyte Rheumatoid Arthritis Rheumatoid Factor Risk Route Safety Severities Small Business Innovation Research Grant Spleen Symptoms System T cell response T-Lymphocyte T-Lymphocyte Epitopes TNF gene Technology Therapeutic Therapeutic Intervention Toxic effect Toxicology Transcriptional Activation Treatment Efficacy Vaccines Work base citrullinated protein clinical application clinical candidate clinical phenotype cytokine cytokine release syndrome design human disease immunogenicity immunoregulation in vivo intraperitoneal joint destruction meetings mouse model nonhuman primate novel novel strategies peptide based vaccine phase 2 study preclinical study programs proteoglycan induced arthritis reduce symptoms response safety study subcutaneous therapeutic vaccine transcription factor tumor necrosis factor-alpha inhibitor

项目摘要

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. To develop a peptide vaccine-based therapy for RA, we used the human proteoglycan (PG)-induced arthritis (PGIA) and the closely related recombinant human PG G1-domain induced arthritis (GIA) models of RA, two mouse models resembling the human disease in their pathologic and genetic features, female preponderance, production of anti-citrullinated protein antibodies and rheumatoid factor. The ligand epitope antigen presentation system (LEAPS™) is a peptide vaccine platform designed to modulate the immune response in an antigen-specific manner. LEAPS peptides are composed of an immune cell binding ligand (ICBL) conjugated to a disease-related peptide (autoepitope). One of the LEAPS conjugates is CEL-4000, which utilizes the DerG ICBL from the human MHC class II β chain that has T helper cell 2 (Th2) polarizing activity, potentially dampening Th1- or Th17-driven autoimmune responses characteristic for RA. In the phase I SBIR study, we showed that CEL-4000, a DerG LEAPS conjugate of the immunodominant epitope (PG70) of the G1 domain of the PG molecule, effectively treats arthritis in the PGIA and GIA models of RA. We hypothesized and then demonstrated that the CEL-4000 LEAPS vaccine modulates the underlying immune responses that drive disease progression in PGIA and GIA. Efficacy was demonstrated by suppressive effects of CEL-4000 on arthritis severity, histopathology of peripheral joints, and cytokine responses. The four Aims of the proposed phase II study are: Aim 1. Determine the in vitro T-cell responses to CEL-4000, the antigen presenting function of CEL-4000-treated dendritic cells (DCs), and whether the conjugate alone and/or conjugate-treated cells alter the differentiation of Th0 cells to distinct Th subsets. Aim 2. Demonstrate therapeutic efficacy of LEAPS-activated DCs or T cells (or a mixture of both) from mice with GIA after ex vivo treatment of these cells with CEL-4000 and adoptive transfer to immunodeficient mice. Aim 3. Extend the CEL-4000 binding and activation studies to rat, non-human primate (NHP), and human peripheral blood cells. Aim 4. Meet with FDA officials, review the CEL-4000 IND-enabling program for in vivo immunogenicity, toxicity and safety, and conduct the relevant and agreed-upon in vivo vaccine treatment studies in NHP. Perform IND-enabling studies using human cells and CEL-4000 in a cytokine release assay as an independent assessment of a potential drug- induced “cytokine storm”. Completion of these Aims will further elucidate the molecular basis for CEL-4000 efficacy and lay the ground work for an IND submission. The proposed studies will further our understanding of the therapeutic immune response elicited by LEAPS peptide- and cell-based vaccines, and initiate the steps towards human trials.

目前，用于治疗类风湿关节炎（RA）的FDA许可的药物主要是减轻症状是通过疼痛管理，一般免疫抑制，或通过拮抗细胞因子（例如 TNF-α。尽管生物疗法最近取得了进步，但这些治疗方法并未解决基础自身免疫性状况。为了开发基于肽疫苗的RA疗法，我们使用了人类蛋白聚糖（PG）诱导的关节炎（PGIA）和密切相关的重组人PG G1障碍诱导关节炎（GIA） RA模型，两个小鼠模型类似于人类疾病的病理和遗传特征，女性优势，抗硝化蛋白抗体和类风湿因子的产生。配体表位抗原表现系统（LAEPS™）是一种肽疫苗平台以抗原特异性方式调节免疫增强响应。飞跃宠物是由免疫细胞组成的结合配体（ICBL）与疾病相关的肽（自动注释）结合。共轭的飞跃之一是 CEL-4000，它利用具有T辅助细胞2（TH2）的人类MHC IIβ链中的Derg ICBL 偏振活性，可能会导致RA的特征性Th1-或Th17驱动的自身免疫反应。在第一阶段的SBIR研究，我们表明CEL-4000是免疫主流表位的DEGR飞跃结合物 PG分子的G1结构域的（PG70）有效地治疗了RA的PGIA和GIA模型中的关节炎。我们假设，然后证明CEL-4000飞跃疫苗可调节基础驱动PGIA和GIA疾病进展的免疫反应。抑制作用证明了功效 CEL-4000对关节炎严重程度，周围关节的组织病理学和细胞因子反应的影响。四个拟议的II期研究的目的是：目标1。确定对CEL-4000的体外T细胞反应，抗原 CEL-4000处理的树突状细胞（DC）的表现功能，以及是否单独轭和/或共轭处理的细胞改变了Th0细胞与不同子集的分化。目标2。证明治疗在离体治疗后，从小鼠的飞跃激活的DC或T细胞（或两者的混合物）的功效这些具有CEL-4000的细胞和适应性转移到免疫缺陷的小鼠。 AIM 3。扩展CEL-4000绑定对大鼠，非人类灵长类动物（NHP）和人类外周血细胞的激活研究。目标4。与 FDA官员，审查用于体内免疫原性，毒性和安全性的CEL-4000辅助计划在NHP中进行相关和商定的体内疫苗治疗研究。进行指定的研究在细胞因子释放测定中使用人类细胞和cel-4000作为对潜在药物的独立评估诱导的“细胞因子风暴”。这些目标的完成将进一步阐明CEL-4000效率的分子基础并置于地面工作以提交。拟议的研究将进一步了解我们对治疗免疫的理解飞跃肽和基于细胞的疫苗引起的反应，并启动了人类试验的步骤。