CLINICAL TRIALS OF CD4 IGG2 AND HUMAB COMBINATIONS

描述：（改编自申请人摘要） 安全有效的被动免疫疗法， 预防HIV-1感染是一个主要目标。 领先的候选人 免疫治疗剂包括广泛中和的人单克隆抗体， 抗体（HuMAb）IgG1b12，与gp120上的CD4结合位点，2F5， gp41和2g12上的保守表位与gp41和2g12上的不连续区域相连 gp120。 此外，CD4-IgG 2表现出有效和广泛的中和作用， HIV-1，包括主要分离株。 第三代CD4- 含有两条CD4-人IgG2重链的基于分子 融合蛋白和CD4-人κ轻链融合体的两条链 蛋白 而IgG1b12、2F5、2G12和CD4-IgG2表现出显著的中和作用， 活动作为单一的代理人，有效的被动发展 免疫治疗可能需要使用两种或多种这些物质的混合物 剂.为了评估其在临床环境中的性能， 我们成立了一个由三个小组组成的联合体， 试剂（IgG1b12-Dennis Burton博士; 2F5和2G12-Hermann博士 Katinger;和，CD4-IgG 2-Drs.Graham Allaway和Paul Maddon）， 协调和加快单一药物的临床试验， 试剂的组合。 这项提案的目标是制造， 准备研究性新药申请并获得监管 美国食品药品监督管理局批准的临床研究 管理，并进行临床试验的代理，以评估 HIV-1感染者耐受性、抗病毒活性和药理学 成人和儿童。 作为我们临床开发计划的一部分，我们 已经安排了一些试点I期临床试验， 在1997 - 98年度， 国家过敏和传染病研究所。 基于其 在临床试验以及体外、离体和 动物研究作为单独的项目在亚伦钻石艾滋病 研究中心和斯克里普斯研究所，我们将选择一个 2、3或4种药物的最佳组合，用于阶段评价 在HIV-1感染的成人和儿童中进行的I/II期临床试验。 如果 成功的，那么在这个建议之后，最佳组合 将被用于大规模的关键临床试验， 该产品的上市许可。

DESCRIPTION: (Adapted from the applicant's abstract) The development of safe and effective passive immunotherapies for the treatment and prevention of HIV-1 infection is a major goal. The leading candidate immunotherapeutics include the broadly neutralizing human monoclonal antibodies (HuMAbs) IgG1b12, to the CD4-binding site on gp120, 2F5 to a conserved epitope on gp41, and 2g12 to a discontinuous region on gp120. In addition, CD4-IgG2 exhibits potent and broad neutralization of HIV-1, including primary isolates. It is a third generation CD4- based molecule containing two chains of a CD4-human IgG2 heavy chain fusion protein and two chains of a CD4-human kappa light chain fusion protein. While IgG1b12, 2F5, 2G12 and CD4-IgG2 exhibit significant neutralization activity as single agents, the development of an effective passive immunotherapy may require the use of mixtures of two or more of these agents. In order to evaluate their performance in the clinical setting, we have formed a consortium of the three groups which developed these agents (IgG1b12 - Dr. Dennis Burton; 2F5 and 2G12 - Dr. Hermann Katinger; and, CD4-IgG2 - Drs. Graham Allaway and Paul Maddon) to coordinate and expedite clinical trials of single agents and combinations of agents. The goal of this proposal is to manufacture, prepare Investigational New Drug applications and gain regulatory approval for clinical investigation from the U.S. Food and Drug Administration, and perform clinical trials of the agents to evaluate tolerability, antiviral activity, and pharmacology in HIV-1 infected adults and children. As part of our clinical development program, we have already arranged for certain pilot Phase I clinical trials to be performed with single agents in 1997-98 under the sponsorship of the National Institute of Allergy and Infectious Diseases. Based on their performance in clinical trials as well as in in vitro, ex vivo, and animal studies performed as separate projects at the Aaron Diamond AIDS Research Center and the Scripps Research Institute, we will select an optimum combination of 2, 3, or 4 of the agents for evaluation in Phase I/II clinical trials in HIV-1 infected adults and children. If successful, then subsequent to this proposal, the optimum combination would be taken to large-scale, pivotal clinical trials in order to gain marketing approval for the product.