Preclinical Development of Full Length Single Chain

全长单链的临床前开发

• 批准号: 8296938
• 负责人: Timothy R Fouts
• 金额: $ 99.71万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296938
• 关键词: ALVAC; Acute; Adjuvant; Adverse event; Animals; Antibodies; Antigens; Biological Assay; Biological Products; Cell Line; Clinical; Clinical assessments; Complex; Cyclic GMP; Data; Development; Dose; Drug Formulations; Ensure; Evaluation; Foundations; GPI-0100; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Humoral Immunities; Immunity; Infection; Ion-Exchange Chromatography Procedure; Length; Link; Macaca mulatta; Methods; Oryctolagus cuniculus; Outcome; Phase; Phase I Clinical Trials; Plasma; Positioning Attribute; Preparation; Procedures; Process; Production; Protocols documentation; Published Comment; Qualifying; Seeds; Solutions; Specific qualifier value; System; Testing; Tissues; Toxicology; Vaccines; Viremia; base; cGMP production; cell bank; immunogenicity; interest; pre-clinical; preclinical safety; public health relevance; rectal; response; safety study; simian human immunodeficiency virus; symposium

DESCRIPTION (provided by applicant): The positive outcome of the RV144 Phase III vaccine trial (the "Thai trial") that tested an ALVAC-HIV/AIDSVAX B/E prime/boost protocol has prompted the field to refocus on humoral immunity as a means of achieving sterilizing immunity. This has also renewed interest in positioned other envelope-based subunit immunogens that may provide a better booster to achieve protection. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicates the conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. In 2 rhesus macaque studies, rhFLSC, a surrogate version of FLSC that contains CD4 derived from rhesus macaques, provided statistically significant protection (rapid clearance of post-acute plasma viremia, as well as potent and sustained suppression of tissue viremia) against rectal challenge with R5 tropic, and heterologus SHIV162P3. This observation indicates that FLSC could provide similar effects in humans and may provide the foundation for an effective vaccine against HIV. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine. To reach this goal, this Fast Track Phase 1 & 2 project has the following aims. Phase 1 Segment Aim 1. Develop pedigreed HEK293 cell lines suitable for the production of FLSC. Aim 2. Identify and optimize release assays. Phase 2 Segment Aim 3. Manufacture lots of material suitable for potency studies (Aim 4) and preclinical toxicology (Aim 5). Aim 4. Confirm that FLSC/adjuvant formulation induces CD4i responses in rabbits. Aim 5. Evaluate FLSC in preclinical safety studies. Overall, the single chain complex has emerged as one of the rare envelope-based subunit immunogen that by itself affords protection against mucosal infection with a completely heterologous SHIV. These findings suggest that single chain complexes should be considered as viable candidates for a vaccine against HIV-1. PUBLIC HEALTH RELEVANCE: The positive outcome of the RV144 Phase III vaccine trial has prompted the field to refocus on defining immunogens that can generate humoral immunity as a means of achieving sterilizing immunity. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicates the conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine.

描述（由申请人提供）：RV144 III 期疫苗试验（“泰国试验”）测试了 ALVAC-HIV/AIDSVAX B/E 初免/加强方案，其积极结果促使该领域重新关注体液免疫作为实现灭菌免疫的一种手段。这也重新引起了人们对定位其他基于包膜的亚基免疫原的兴趣，这些免疫原可能提供更好的增强剂来实现保护。其中一种免疫原是全长单链 (FLSC)，它是一种 gp120 人 CD4 融合体，可复制保守的包膜-CD4 复合物，这是所有 HIV 分离株在感染过程中必须实现的关键过渡状态。在两项恒河猴研究中，rhFLSC（FLSC 的替代版本，含有源自恒河猴的 CD4）针对 R5 tropic 和异源 SHIV162P3 的直肠攻击提供了统计学上显着的保护（快速清除急性后血浆病毒血症，以及有效且持续地抑制组织病毒血症）。这一观察结果表明，FLSC 可以在人类中产生类似的效果，并可能为有效的 HIV 疫苗奠定基础。因此，该项目的目标是启动 FLSC 的临床前开发，为 I 期临床试验的评估做好准备，作为下一步辨别 FLSC 是否可以成为有效的 HIV 疫苗的步骤。为了实现这一目标，快速通道第一期和第二期项目有以下目标。第一阶段的目标 1. 开发适合生产 FLSC 的纯系 HEK293 细胞系。目标 2. 识别并优化释放测定。第 2 阶段细分目标 3。制造大量适合效力研究（目标 4）和临床前毒理学（目标 5）的材料。目标 4. 确认 FLSC/佐剂制剂可诱导兔子的 CD4i 反应。目标 5. 在临床前安全性研究中评估 FLSC。总体而言，单链复合物已成为一种罕见的基于包膜的亚基免疫原，其本身可提供针对完全异源 SHIV 粘膜感染的保护作用。这些发现表明单链复合物应被视为 HIV-1 疫苗的可行候选者。 公共卫生相关性：RV144 III 期疫苗试验的积极结果促使该领域重新关注定义可产生体液免疫的免疫原，作为实现灭菌免疫的一种手段。其中一种免疫原是全长单链 (FLSC)，它是一种 gp120 人 CD4 融合体，可复制保守的包膜-CD4 复合物，这是所有 HIV 分离株在感染过程中必须实现的关键过渡状态。因此，该项目的目标是启动 FLSC 的临床前开发，为 I 期临床试验的评估做好准备，作为下一步辨别 FLSC 是否可以成为有效的 HIV 疫苗的步骤。