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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，FDA许可的用于治疗类风湿性关节炎（RA）的药物主要集中在缓解类风湿性关节炎（RA）。通过疼痛管理、一般免疫抑制或通过拮抗细胞因子， TNF-α。尽管最近在生物疗法方面取得了进展，但这些治疗并不能解决潜在的问题。自身免疫性疾病为了开发一种基于肽疫苗的治疗RA的方法，我们使用了人蛋白聚糖（PG）诱导的关节炎（PGIA）和密切相关的重组人PG G1结构域诱导的关节炎（GIA） RA模型，两种在病理和遗传特征上与人类疾病相似的小鼠模型，雌性优势，抗瓜氨酸化蛋白抗体和类风湿因子的产生。配体表位抗原呈递系统（LEAPS™）是肽疫苗平台，其被设计成以抗原特异性方式调节免疫应答。LEAPS肽由免疫细胞组成，结合配体（ICBL）缀合至疾病相关肽（自身表位）。LEAPS结合物之一是 CEL-4000，其利用来自具有T辅助细胞2（Th 2）的人MHC II类β链的DerG ICBL 极化活性，可能抑制Th 1或Th 17驱动的RA特有的自身免疫反应。在在I期SBIR研究中，我们发现免疫显性表位的DerG LEAPS缀合物CEL-4000 PG分子的G1结构域的多肽（PG 70），有效地治疗RA的PGIA和GIA模型中的关节炎。我们假设并证明了CEL-4000 LEAPS疫苗调节了潜在的免疫应答驱动PGIA和GIA中的疾病进展。有效性通过抑制 CEL-4000对关节炎严重程度、外周关节的组织病理学和细胞因子应答的影响。四拟议的II期研究的目标是：目标1。测定对抗原CEL-4000的体外T细胞应答图4显示了经CEL-4000处理的树突状细胞（DC）的呈递功能，以及单独的缀合物和/或缀合物处理的细胞改变了Th 0细胞向不同Th亚群的分化。目标二。显示治疗效果来自患有GIA的小鼠的LEAPS激活的DC或T细胞（或两者的混合物）在离体治疗后的功效这些细胞与CEL-4000和过继转移到免疫缺陷小鼠。目标3.扩展CEL-4000绑定以及对大鼠、非人灵长类动物（NHP）和人外周血细胞的活化研究。目标4。会见 FDA官员，审查CEL-4000 IND使能项目的体内免疫原性、毒性和安全性，在NHP中进行相关和商定的体内疫苗治疗研究。进行IND启用研究在细胞因子释放试验中使用人细胞和CEL-4000作为潜在药物的独立评估，诱发“细胞因子风暴”。这些目标的完成将进一步阐明CEL-4000功效的分子基础，为IND提交工作。拟议的研究将进一步加深我们对治疗性免疫的理解。 LEAPS疫苗和基于细胞的疫苗引起的免疫应答，并启动人体试验的步骤。