Development of a multimeric CD40 ligand vaccine adjuvant

多聚体CD40配体疫苗佐剂的开发

• 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
• 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

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(申请人提供)：CD40配体(CD40L或CD154)被广泛认为是免疫系统最重要的内源性激活剂之一。CD40L刺激树突状细胞(DC)启动强烈的CD8+T细胞反应。然而，尽管进行了多次尝试，但没有一种形式的CD40L获得临床使用许可。为了解决这一问题，该项目将推进CD40L的高活性、可溶形式的开发。这种新的蛋白质是由Acrp30(一种天然血清蛋白)的主体与CD40L的胞外结构域融合而成的。最终的蛋白Acrp30-CD40L或“MegaCD40L”已被证实是疫苗诱导的CD8+T细胞反应的高效佐剂。在这个SBIR第一阶段项目中，MegaCD40L将通过开发cGMP CHO细胞的研究细胞库来向临床推进，这些细胞库可以产生人和小鼠的MegaCD40L。所产生的蛋白质将使用可以扩大到工业生产的方法纯化到均一。为了证明这种新佐剂的实用性，MegaCD40L将在一种名为“交叉质点-短间隔增强”的小鼠疫苗接种系统中进行测试，该系统由该项目的顾问John Harty博士(爱荷华大学)开发。在此疫苗接种方案中，首先用包被抗原的PLGA微球接种小鼠，7天后再用抗原+MegaCD40L+Poly(I：C)加强免疫。预计这将产生真正巨大的抗原特异性CD8+T细胞反应，这对于预防流感、疟疾和生物防御剂引起的感染的疫苗将是重要的。在该项目结束时，MegaCD40L将准备好支持BLA的cGMP蛋白质制造和正式毒性测试，作为这种令人兴奋的新疫苗佐剂进行人体试验的下一步。