POST EXPOSURE PROPHYLAXIS AGAINST HIV 1 BY CD4 IGG2

在I期项目中，我们证明了一种新的基于CD 4的蛋白质， CD 4-IgG 2具有优异的特性，可进一步开发为 HIV-1感染的预防剂，以保护个体免受 环境中的感染，如垂直和职业接触， 病毒CD 4-IgG 2相对于HIV免疫球蛋白（HIVIG）的主要优势 和单克隆抗体的病毒是，CD 4-IgG 2中和所有 HIV-1菌株，包括病毒的主要分离株。期间 在I期，我们证明了CD 4-IgG 2在体外中和了一种免疫抑制剂， 一组来自不同遗传分支的28个主要HIV-1分离株。 此外，CD 4-IgG 2中和未稀释的病毒血症血浆中的HIV-1， 离体测定。最后，我们证明了CD 4-IgG 2保护hu-PBL-T细胞。 SCID小鼠免受HIV-1原代分离株感染。 这是第一 在动物中证明对主要HIV-1分离株的保护作用 使用任何免疫抑制剂或抗逆转录病毒剂。 在II期项目中，我们将继续开发CD 4-IgG 2。 首先，我们将扩大生产过程， 蛋白质。我们将测试CD 4-IgG 2与广泛的 中和HIV-1的mAb，用于协同抑制病毒。 将在新型HIV-1包膜中分析组合 糖蛋白介导的膜融合试验和体外 使用原代HIV-1分离株的中和试验。我们将比较 单独的CD 4-IgG 2相对于最佳的CD 4-IgG 2-mAb的保护能力 在用几种主要HIV-1攻击的hu-PBL-SCID小鼠中的组合 分离株和用猴-人免疫缺陷病毒攻击的猕猴 含有HIV-1原代分离株gp 120/gp 41的SHIV病毒。 一种安全有效的HIV-1预防剂的研制 是一个紧迫的公共卫生优先事项。第二阶段的总体目标 项目是确定CD 4-IgG 2或CD 4-IgG 2和 广泛中和的单克隆抗体，可以保护免受感染的主要 HIV-1分离株的最佳可用动物模型。如果成功， 第二阶段项目将构成第三阶段临床试验的基础。 第三阶段。 拟定的商业应用：开发CD 4-IgG 2作为 抗HIV-1感染的预防剂。

In the Phase I project, we demonstrated that a novel CD4-based protein, CD4-IgG2, has excellent properties for further development as a prophylactic agent for HIV-1 infection, to protect individuals from infection in settings such as vertical and occupational exposure to the virus. The major advantage of CD4-IgG2 over HIV immune globulin (HIVIG) and monoclonal antibodies to the virus is that CD4-IgG2 neutralizes all stains of HIV-1, including primary isolates of the virus. During the Phase I period, we demonstrated that CD4-IgG2 neutralized in vitro a panel of 28 primary HIV-1 isolates from different genetic clades. Moreover, CD4-IgG2 neutralized HIV-1 in undiluted viremic plasma in an ex vivo assay. Finally, we demonstrated that CD4-IgG2 protects hu-PBL- SCID mice from infection by primary HIV-1 isolates. This is the first demonstration of protection against primary HIV-1 isolates in an animal model using any immunotherapeutic or antiretroviral agent. In the Phase II project, we will continue the development of CD4-IgG2. First, we will scale-up the production process and generate one gram of the protein. We will test combinations of CD4-IgG2 with broadly neutralizing mAbs to HIV-1 for synergistic inhibition of the virus. Combinations will be analyzed in both a novel HIV-1 envelope glycoprotein-mediated membrane fusion assay and in an in vitro neutralization assay using primary HIV-1 isolates. We will then compare the protective ability of CD4-IgG2 alone versus the optimal CD4-IgG2-mAb combination in hu-PBL-SCID mice challenged with several primary HIV-1 isolates, and macaques challenged with simian-human immunodeficiency virus (SHIV) containing gp120/gp41 of a primary HIV-1 isolate. The development of a safe and effective prophylactic agent against HIV-1 is an urgent public health priority. The overall goal of the Phase II project is to determine whether CD4-IgG2, or combinations of CD4-IgG2 and broadly neutralizing mAbs, can protect against infection by primary isolates of HIV-1 in the best available animal models. If successful, the Phase II project will form the basis of clinical trials during the Phase III period. PROPOSED COMMERCIAL APPLICATION: Development of a CD4-IgG2 as a prophylactic agent against HIV-1 infection.