BROAD POSTEXPOSURE INHIBITION OF HIV BY ANTIBODIES

抗体对 HIV 的广泛暴露后抑制

• 批准号: 2771653
• 负责人: Carl Veith Hanson
• 金额: $ 32.45万
• 依托单位: PUBLIC HEALTH FOUNDATION ENTERPRISES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2771653
• 关键词: AIDS therapy; NOD mouse; SCID mouse; antibody neutralization test; chemokine; clinical research; clinical trial phase I; cytokine receptors; drug screening /evaluation; human immunodeficiency virus; human subject; human therapy evaluation; immunotherapy; monoclonal antibody; neutralizing antibody

DESCRIPTION (Adapted from the applicant's abstract) Post-exposure immunoprophylaxis will be achieved only when the following requisite characteristics of an HIV monoclonal antibody are realized: neutralization of globally diverse HIV isolates; lack of toxicity; excellent pharmacokinetics; and reproducible properties as determined by sensitive in vitro assays. The goal of the proposed project is to address these factors by developing several improved approaches to neutralizing antibody assay methodology, and by applying the improved assays to the characterization of a novel monoclonal antibody which inhibits a wide range of HIV variants by targeting the host cell. Other monoclonal antibodies having broad HIV neutralizing activities will also be included for characterization by the improved assays so as to allow formation of optimal monoclonal antibody mixtures, if required. In a long-term collaboration between the Principal Investigator and United Biomedical, Inc., a proprietary anti-host cell monoclonal antibody ("B4") has been developed and partially characterized. B4 is directed against a complex comprising CD4 in association with domains of multiple chemokine receptors. In preliminary studies, it has successfully neutralized SIV, SHIV, HIV-2 and representatives of multiple subtypes (clades) of HIV-1, even when the antibody is added after infection of the cells by a PBMC-grown primary isolate. The antibody, which is not cytotoxic in vitro, has also protected humanized mice when added up to four hours after HIV challenge. In the proposed studies, the murine antibody will be humanized in collaboration with the MRC Collaborative Centre in London, subjected to complete toxicological testing, and, in the final year of the project, evaluated in human clinical trials. The improved neutralizing antibody assays will be used to further characterize both the murine and human forms of the antibody to help monitor the clinical trial.

描述 （改编自申请人的摘要）暴露后免疫预防将 只有当艾滋病毒具有以下必要特征时才能实现 实现单克隆抗体：中和全球多样化的艾滋病毒 隔离；缺乏毒性；优良的药代动力学；并且可重复 通过敏感的体外测定确定的特性。 的目标 拟议的项目是通过开发几种改进的方法来解决这些因素 中和抗体测定方法的方法，并通过应用 改进了新型单克隆抗体表征的测定方法 通过靶向宿主细胞来抑制多种 HIV 变体。 其他 具有广泛的 HIV 中和活性的单克隆抗体也将 包括通过改进的测定进行表征，以便允许 如果需要，形成最佳的单克隆抗体混合物。 在一个 首席研究员与United的长期合作 Biomedical, Inc.，一种专有的抗宿主细胞单克隆抗体（“B4”） 已经开发并部分表征。 B4针对的是 包含与多种趋化因子结构域相关的 CD4 的复合物 受体。 在初步研究中，它已成功中和SIV， SHIV、HIV-2 和 HIV-1 多个亚型（进化枝）的代表，甚至 当细胞被 PBMC 生长的细胞感染后添加抗体时 主要分离株。 该抗体在体外没有细胞毒性，也具有 HIV攻击后四小时内，可保护人源化小鼠。 在拟议的研究中，鼠源抗体将被人源化 与伦敦 MRC 合作中心合作， 完成毒理学测试，并且在项目的最后一年， 在人体临床试验中进行评估。 改进的中和抗体 检测将用于进一步表征鼠类和人类形式 抗体以帮助监测临床试验。