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（由申请方提供）：RV 144 III期疫苗试验（“泰国试验”）的阳性结果（该试验测试了ALVAC-HIV/AIDSVAX B/E初免/加强方案）促使该领域重新关注体液免疫作为实现灭菌免疫的手段。这也重新引起了人们对定位其他基于酶的亚单位免疫原的兴趣，这些免疫原可能提供更好的增强剂以实现保护。一种这样的免疫原是全长单链（FLSC），一种gp 120人CD 4融合体，其复制保守的CD 4-CD 4复合物，这是所有HIV分离株在感染期间必须实现的关键过渡状态。在2项恒河猴研究中，rhFLSC（一种含有源自恒河猴的CD 4的FLSC替代品）针对R5嗜性和异源SHIV 162 P3直肠攻毒提供了统计学显著性保护（快速清除急性后血浆病毒血症，以及有效和持续抑制组织病毒血症）。这一观察结果表明，FLSC可以在人类中提供类似的效果，并可能为有效的艾滋病毒疫苗提供基础。因此，本项目的目标是启动FLSC的临床前开发，为其在I期临床试验中的评估做准备，作为识别FLSC是否可以成为有效的HIV疫苗的下一步。为了实现这一目标，这个快速通道第1和第2阶段项目有以下目标。阶段1细分目标1.开发适用于生产FLSC的HEK 293细胞系。目标二。识别和优化放行检测。第二阶段目标3.生产适用于效价研究（目标4）和临床前毒理学（目标5）的材料批次。目标4。确认FLSC/佐剂制剂诱导兔的CD 4 i反应。目标5。在临床前安全性研究中评价FLSC。总的来说，单链复合物已经成为一种罕见的基于SIV的亚单位免疫原，其本身提供针对完全异源SHIV的粘膜感染的保护。这些研究结果表明，单链复合物应被视为可行的候选人的疫苗对HIV-1。 公共卫生关系：RV 144 III期疫苗试验的积极结果促使该领域重新关注定义可以产生体液免疫的免疫原，作为实现杀菌免疫的手段。一种这样的免疫原是全长单链（FLSC），一种gp 120人CD 4融合体，其复制保守的CD 4-CD 4复合物，这是所有HIV分离株在感染期间必须实现的关键过渡状态。因此，本项目的目标是启动FLSC的临床前开发，为其在I期临床试验中的评估做准备，作为识别FLSC是否可以成为有效的HIV疫苗的下一步。