Preclinical Development of Full Length Single Chain

全长单链的临床前开发

• 批准号: 8013359
• 负责人: Timothy R Fouts
• 金额: $ 29.93万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013359
• 关键词: 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; 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期疫苗试验的积极结果（“泰国试验”）测试了ALVAC-HIV/AIDSVAX B/E PRIME/BOOST协议，促使该领域重新集中于体液免疫，以作为实现消毒免疫力的手段。这也引起了对定位其他基于信封的亚基免疫原的兴趣，这些免疫原子可能为获得保护提供更好的助推器。这样的免疫原是全长单链（FLSC）GP120人CD4融合，它复制了保守的包膜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2个恒河猕猴研究中，RHFLSC是FLSC的代孕版本，其中包含源自恒河猕猴的CD4，提供了统计学上的显着保护（急性急性血浆病毒血症的迅速清除，以及对组织病毒的有效抑制和持续抑制），以防止对R5 Tropic和Netropic Shivs Shivs Shiv162p3的直肠挑战。该观察结果表明，FLSC可以在人类中提供类似的影响，并可能为对艾滋病毒的有效疫苗提供基础。因此，该项目的目的是启动FLSC的临床前开发，以准备在I期临床试验中评估其作为下一步的评估，以辨别FLSC是否可以是有效的HIV疫苗。为了实现这一目标，这个快速阶段的1＆2项目具有以下目标。第1阶段段目标1。开发适合于FLSC生产的建HEK293细胞系。目标2。确定并优化发布分析。第2阶段的目标3。生产许多适合效力研究（AIM 4）和临床前毒理学（AIM 5）的材料。 AIM 4。确认FLSC/辅助配方会诱导兔子的CD4I反应。 AIM 5。评估临床前安全研究中的FLSC。总体而言，单链复合物已成为基于包膜的稀有亚基免疫原之一，它本身可以通过完全异源SHIV保护粘膜感染。这些发现表明，应将单链复合物视为针对HIV-1的疫苗的可行候选。 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点关注可以定义可以产生体液免疫的免疫原子，以作为实现无菌免疫力的一种手段。这样的免疫原是全长单链（FLSC）GP120人CD4融合，它复制了保守的包膜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，该项目的目的是启动FLSC的临床前开发，以准备在I期临床试验中评估其作为下一步的评估，以辨别FLSC是否可以是有效的HIV疫苗。