Development of a multimeric CD40 ligand vaccine adjuvant

多聚体CD40配体疫苗佐剂的开发

基本信息

批准号：
8715683
负责人：
Richard Syd Kornbluth
金额：
$ 29.34万
依托单位：
MULTIMERIC BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715683
关键词：
Acids Adjuvant Advanced Development Agonist Antibodies Antigens Biological Response Modifier Therapy Biotechnology Blood CD40 Ligand CD8B1 gene Cell Line Cells Centrifugation Chinese Hamster Ovary Cell Chromatography Chronic Clinic Clinical Clinical Trials Codon Nucleotides Communities Cross-Priming Cyclic GMP Dendritic Cells Development Extracellular Domain Filtration Freedom Funding Grant Harvest Human Immune response Immune system Immunologic Adjuvants Immunologist In Vitro Infection Infectious Agent Influenza Investments Ion-Exchange Chromatography Procedure Iowa Laboratories Lead Legal patent Licensing Life Ligands Malaria Malignant Neoplasms Mediation Memory Methods Microbe Microspheres Mus Ovalbumin Pathway interactions Patients Phase Phase I Clinical Trials Plasmids Polishes Poly I-C Problem Solving Process Production Proteins Protocols documentation Research Research Personnel Risk Roller Bottle Scheme Serum Proteins Serum-Free Culture Media Small Business Innovation Research Grant Stimulus System T cell response T-Lymphocyte TLR3 gene TNF gene TNFRSF5 gene TNFSF5 gene Technology Testing Toxicity Tests Ultrafiltration Universities Vaccinated Vaccination Vaccine Adjuvant Vaccine Design Vaccines Virus Diseases biodefense cell bank design drug development fast protein liquid chromatography interest method development novel novel vaccines prevent public health relevance receptor research study response scale up therapeutic protein vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): CD40 ligand (CD40L or CD154) is widely recognized as one of the most important endogenous activators of the immune system. In particular, CD40L stimulates dendritic cells (DCs) to initiate strong CD8+ T cell responses. However, despite several attempts, no form of CD40L has been licensed for clinical use. To solve this problem, this project will advance the development of a highly active, soluble form of CD40L. This novel protein is made by fusing the body of Acrp30 (a natural serum protein) with the extracellular domain of CD40L. The final protein, Acrp30-CD40L or "MegaCD40L," has been validated as a highly effective adjuvant for vaccine-induced CD8+ T cell responses. In this SBIR Phase 1 project, MegaCD40L will be advanced toward the clinic by developing research cell banks of cGMP CHO cells that produce human and murine MegaCD40L. The resulting proteins will be purified to homogeneity using methods that can be scaled up to industrial production. To prove the utility of this new adjuvant, MegaCD40L will be tested in a mouse vaccination system called "cross-prime-short interval boost" as developed by Dr. John Harty (University of Iowa), a Consultant to the project. In this vaccination protocol, mice are first vaccinated with PLGA microspheres coated with antigen followed 7 days later by boosting with antigen plus MegaCD40L plus poly(I:C). This is anticipated to generate a truly enormous antigen-specific CD8+ T cell response that would be important for vaccines against influenza, malaria, and infections caused by biodefense agents. At the conclusion of this project, MegaCD40L will be ready for BLA-enabling cGMP protein manufacturing and formal toxicity testing as the next steps toward a human trial with this exciting new vaccine adjuvant.

描述（由申请人提供）：CD40配体（CD40L或CD154）被广泛认为是免疫系统中最重要的内源性激活剂之一。特别是，CD40L刺激树突状细胞（DC）启动强烈的CD8+ T细胞反应。但是，尽管有多次尝试，但CD40L的任何形式均未获得临床使用许可。为了解决这个问题，该项目将推动CD40L高度活跃，可溶性形式的开发。这种新型蛋白是通过将ACRP30（天然血清蛋白）与CD40L的细胞外结构域融合而成的。最终的蛋白质ACRP30-CD40L或“ MEGACD40L”已被验证为疫苗诱导的CD8+ T细胞反应的高效辅助物。在这个SBIR 1阶段项目中，MEGACD40L将通过开发产生人类和鼠MegACD40L的CGMP CHO细胞的研究细胞库来向诊所发展。所得的蛋白质将使用可以扩展到工业生产的方法将其纯化为同质性。为了证明这种新佐剂的实用性，MEGACD40L将在该项目的顾问John Harty（爱荷华大学）（爱荷华大学）开发的一种称为“交叉临时间隔助推器”的小鼠疫苗接种系统中进行测试。在该疫苗接种方案中，首先用含有抗原的PLGA微球接种小鼠，然后在7天后使用抗原加MEGACD40L加Poly（I：C），从而提高了抗原。预计这将产生真正的巨大抗原特异性CD8+ T细胞反应，这对于针对流感，疟疾的疫苗和由生物脱脂剂引起的感染至关重要。在该项目结束时，MEGACD40L将准备好使用这种令人兴奋的新疫苗辅助剂，以促进BLA的CGMP蛋白质制造和形式上的毒性测试。