GMP MANUFACTURE OF CLINICAL GRADE THERAPEUTIC VACCINE FOR THE TREATMENT OF PATIENTS WITH CHRONIC HBV

用于治疗慢性乙型肝炎患者的临床级治疗疫苗的 GMP 生产

• 批准号: 10602445
• 负责人: Valerian Nakaar
• 金额: $ 114.03万
• 依托单位: CAROGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602445
• 关键词: Address; Affect; Agreement; Animals; Antibodies; Antigens; Biological Assay; Biological Markers; CD8-Positive T-Lymphocytes; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Contracts; Dependovirus; Development; Disease; Dose; Drug Kinetics; Eligibility Determination; Engineering; Excipients; Feasibility Studies; Feedback; Formulation; Funding; GMP lots; Glycoproteins; Goals; Good Manufacturing Process; Grant; Health; Hepatitis B; Hepatitis B Core Antigen; Hepatitis B Surface Antigens; Hepatitis B Virus; Human; Immunotherapy; Investigational Drugs; Investigational New Drug Application; Legal patent; Liver; Liver diseases; Methods; Mus; Patients; Performance; Persons; Phase; Phase I Clinical Trials; Positioning Attribute; Primary carcinoma of the liver cells; Process; Production; Progress Reports; Protocols documentation; Quality Control; Regimen; Research Contracts; Research Design; Risk; Risk Factors; Running; Safety; Serum; Small Business Innovation Research Grant; T cell response; Testing; Toxic effect; Toxicology; United States Food and Drug Administration; United States National Institutes of Health; Vaccines; Validation; Vesicle; Viral Antigens; Virus; Virus Diseases; Virus Replication; Work; analytical method; assay development; cell bank; design; immunogenicity; innovation; manufacture; manufacturing organization; manufacturing process development; mouse model; novel; novel strategies; pharmacokinetics and pharmacodynamics; phase 1 study; phase 1 testing; plasmid DNA; preclinical study; prevent; product development; programs; promoter; research clinical testing; scale up; seroconversion; stability testing; therapeutic vaccine; vector

The ultimate objective of this SBIR project is to develop an immunotherapy based on our recently patented virus-like vesicle (VLV) platform for the treatment of chronic hepatitis B (CHB). The goal of this project is to complete preclinical studies and product development of the CARG-201 vaccine. We have designed this vector to achieve a functional cure in CHB patients, characterized by a sustained loss of hepatitis B surface antigen (HBsAg) (with or without HBsAg antibody seroconversion), using our VLV-based hepatitis B virus (HBV) therapies. We have developed a therapeutic vaccine capable of inducing virus-specific CD8+ T cells that clear HBV infection. As detailed in the progress report (see attached RPRR), we have attained the majority of the Phase II milestones. Using a VLV dual promoter and a glycoprotein switch, we have enhanced efficacy, as demonstrated in an adeno-associated virus (AAV) mouse model of persistent HBV. We have generated CARG-201 harboring both MHBs and HBcAg antigens, which can control HBV replication, as evidenced by reduced serum HBsAg levels in mice. The reduction in serum biomarker levels in more than 80% AAV-HBV mice with high antigenemia is highly significant as it indicates that CARG-201 can break tolerance and drive T-cell responses to HBV antigens. As this is the first attempt to produce good manufacturing practice (GMP)-grade VLVs, our task is critically important and requires innovative approaches. The Food and Drug Administration (FDA) provided pre-investigational new drug (IND) feedback on CARG-201 in April 2019, and we have addressed all of their concerns. The FDA agreed with our proposed plan on the animal toxicology program, GMP manufacturing methods, and quality control testing. The FDA also provided positive feedback on our clinical study objectives/endpoints and our Phase 1 study design, including the dosing regimen and patient eligibility criteria. Thus, with the completion of GMP manufacturing and animal toxicology studies, we are now progressing CARG-201 to clinical trial(s). To complete the studies required by the FDA for an IND application, we propose the following specific aims in Phase IIb: Aim 1. Complete safety, non-clinical toxicology, and pharmacokinetics studies of CARG-201. Aim 2. Conduct product development studies of CARG- 201, including manufacturing process development, scale-up feasibility studies, purification, analytic assay development, and formulation and stability studies. Aim 3. Initiate GMP manufacture and release of clinical-grade CARG-201 material and submit an IND application to support Phase I evaluation. IMPACT: This project addresses the urgent unmet need for a therapeutic vaccine for CHB, harnessing work previously funded by an NIH SBIR Phase I and II grant. This project is well positioned to yield sustained and powerful progress towards the development of an efficacious immunotherapy for CHB.

这个SBIR项目的最终目标是基于我们最近的新免疫疗法 用于治疗慢性丙型肝炎（CHB）的专利病毒样囊泡（VLV）平台。目标 这个项目是完成Carg-201的临床前研究和产品开发 疫苗。我们设计了此矢量以实现CHB患者的功能治疗，以表征 肝炎表面抗原（HBSAG）的持续损失（有或没有HBSAG抗体 血清转化），使用我们的基于VLV的丙型肝炎病毒（HBV）疗法。我们已经开发了 能够诱导清除HBV感染的病毒特异性CD8+ T细胞的治疗疫苗。作为 在进度报告中详细介绍（请参阅附带的RPRR），我们达到了大部分阶段 II里程碑。使用VLV双启动子和糖蛋白开关，我们的功效增强了 如持续HBV的腺相关病毒（AAV）小鼠模型所示。我们有 产生的Carg-2012携带MHB和HBCAG抗原，可以控制HBV 复制，如小鼠的血清HBSAG水平降低所证明。血清减少 高度高抗原血症的80％以上AAV-HBV小鼠的生物标志物水平非常重要，因为 这表明CARG-201可以打破公差并驱动对HBV抗原的T细胞反应。作为 这是生产良好制造实践（GMP） - 级VLV的第一次尝试，我们的任务是 至关重要，需要创新的方法。食品药品监督管理局（FDA） 2019年4月提供了对Carg-2011的投票前新药（IND）的反馈，我们有 解决了他们所有的关注。 FDA同意我们针对动物毒理学的计划 程序，GMP制造方法和质量控制测试。 FDA也提供了 对我们的临床研究目标/终点的积极反馈和我们的第一阶段研究设计， 包括给药方案和患者资格标准。因此，随着GMP的完成 制造业和动物毒理学研究，我们现在正在Carg-2012 试验。为了完成FDA为IND应用所需的研究，我们提出了 在IIB期中的具体目标：AIM 1。完全安全，非临床毒理学和 Carg-201-2011的药代动力学研究。目标2。进行carg-的产品开发研究 201，包括制造过程开发，扩大可行性研究，纯化， 分析测定开发以及制定和稳定性研究。目标3。发起GMP 制造和释放临床级Carg-2011材料，并提交IND申请 支持I阶段评估。影响：该项目解决了对A的紧急需求 用于CHB的治疗疫苗，利用先前由NIH SBIR I和II资助的工作 授予。该项目的位置很好，可以在 开发CHB有效的免疫疗法。