ANTI CD4 BASED THERAPIES FOR HIV INFECTION

基于抗 CD4 的 HIV 感染疗法

• 批准号: 6277839
• 负责人: KEITH A REIMANN
• 金额: $ 8.77万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6277839
• 关键词: AIDS; Mammalia; Primates; drug /agent; immunology; infection; inflammation; lymphatic system; virus

Certain monoclonal antibodies (mAb) directed against CD4 can efficiently block HIV-1 replication in vitro. to explore CD4-directed passive immunotherapy for prevention or treatment of AIDS-virus infection, we previously examined the biological activity of a nondepleting CD4-specific murine mAb, mu5A8. This mAb, specific for domain 2 of CD4 blocks HIV-1 replication at a post-gp120/CD4 binding step. When administered to normal rhesus monkeys, all CD4+ target cells were coated with antibody, yet no cell clearance or measurable immunosuppression occurred. However, strong anti-mouse Ig responses rapidly developed in all monkeys. In the present study, we report a successfully humanized form of mu5A8 (hu5A8) that retains binding to both human and monkey CD4 and anti-AIDS virus activity. When administered intravenously to normal rhesus monkeys, hu5A8 bound to all target CD4+ cells without depletion and showed a significantly longer plasma half-life than mu5A8. Nevertheless, an anti-hu5A8 response directed predominantly against V region determinants did eventually appear within two to four weeks in most animals. However, when hu5A8 was administered to rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques, anti-hu5A8 antibodies were not detected. Repeated administration of hu5A8 in these animals resulted in sustained plasma levels and CD4+ cell coating with humanized antibody for six weeks. These studies demonstrate the feasibility of chronic administration of CD4-specific mAb as a potential means of treating or preventing HIV-1 infection.

某些针对CD 4的单克隆抗体（mAb）可 在体外有效地阻断HIV-1复制。 探索CD 4导向的 用于预防或治疗艾滋病病毒的被动免疫疗法 感染时，我们之前检查了一种 非消耗性CD 4特异性鼠mAb，mu 5A 8。 该mAb，特异于 CD 4结构域2在gp 120/CD 4结合后阻断HIV-1复制 步 当给予正常恒河猴时，所有CD 4+靶向 细胞用抗体包被，但没有细胞清除或可测量的 发生免疫抑制。 然而，强烈的抗小鼠IG应答 在所有的猴子身上迅速发展。 在本研究中，我们报告了一个 mu 5A 8（hu 5A 8）的成功人源化形式，保留与 人和猴的CD 4和抗艾滋病病毒活性。 当 静脉内给予正常恒河猴，hu 5A 8结合到 所有靶向CD 4+细胞均未耗竭， 血浆半衰期比mu 5A 8长。 然而，抗hu 5A 8 主要针对V区决定簇的反应 在大多数动物体内会在两到四周内出现。 然而，在这方面， 当将hu 5A 8给予慢性感染的恒河猴时， 与猕猴的猴免疫缺陷病毒，抗hu 5A 8 未检测到抗体。 重复施用hu 5A 8， 这些动物导致持续的血浆水平和CD 4+细胞 用人源化抗体包被六周。 这些研究 证明长期给予CD 4特异性 mAb作为治疗或预防HIV-1感染的潜在手段。