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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批准的用于治疗类风湿性关节炎(RA)的药物主要集中在缓解症状，要么通过疼痛控制，要么通过全身免疫抑制，要么通过拮抗细胞因子，如肿瘤坏死因子α。尽管最近在生物疗法方面取得了进展，但这些治疗方法并没有解决潜在的自身免疫性疾病。为了开发一种基于多肽疫苗的RA治疗方法，我们使用了人类蛋白多糖 (PG)诱导的关节炎(PGIA)及其密切相关的重组人PG G1结构域诱导的关节炎(GIA) 类风湿性关节炎模型，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，产生抗瓜氨酸蛋白抗体和类风湿因子。配体表位抗原呈递系统(LEAPS™)是一个多肽疫苗平台，旨在以抗原特异性的方式调节免疫反应。LEAPS多肽由免疫细胞组成与疾病相关的多肽(自身表位)结合的结合配体(ICBL)。Leap的其中一个共享物是 CEL-4000，它利用来自人类MHC II类β链的DERG ICBL，具有辅助性T细胞2(Th2) 两极分化的活动，潜在地抑制Th1或Th17驱动的RA特有的自身免疫反应。在 I期SBIR研究表明，CEL-4000是一种免疫优势表位的LEAP结合物 PG分子的G1结构域(PG70)有效地治疗类风湿关节炎(PGIA)和类风湿性关节炎(GIA)模型。我们假设并证明了CEL-4000 LEAPS疫苗调节潜在的在PGIA和GIA中推动疾病进展的免疫反应。有效的方法是通过抑制 CEL-4000对关节炎严重程度、周围关节组织病理学和细胞因子反应的影响。四个拟议的第二阶段研究的目的是：目的1.测定T细胞对CEL-4000抗原的体外反应 CEL-4000处理的树突状细胞(DC)的呈递功能，以及结合物是否单独和/或结合物处理的细胞改变了Th0细胞分化为不同的Th亚群。目标2.展示治疗效果 LEAPS激活的DC或T细胞(或两者的混合物)对GIA小鼠体外治疗后的疗效这些细胞与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(NHP)和人类外周血细胞的激活研究。目标4.与 FDA官员，审查CEL-4000 IND使能计划体内免疫原性、毒性和安全性，以及在国家卫生研究院进行相关的和商定的体内疫苗治疗研究。执行启用IND的研究在细胞因子释放试验中使用人类细胞和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疗效的分子基础并奠定基础为IND提交的文件工作。建议的研究将进一步加深我们对治疗性免疫的理解。 Leapps多肽和细胞疫苗引起的反应，并启动人体试验的步骤。