ANTI CD4 BASED THERAPIES FOR HIV INFECTION

基于抗 CD4 的 HIV 感染疗法

• 批准号: 6116605
• 负责人: KEITH A REIMANN
• 金额: $ 6.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6116605
• 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）可以有效地阻断HIV-1在体外的复制。 为了探索用于预防或治疗艾滋病病毒感染的CD 4导向的被动免疫疗法，我们先前检测了非消耗性CD 4特异性鼠单克隆抗体mu 5A 8的生物学活性。 该mAb对CD 4结构域2具有特异性，可在gp 120/CD 4结合步骤后阻断HIV-1复制。 当给予正常恒河猴时，所有CD 4+靶细胞都被抗体包被，但没有发生细胞清除或可测量的免疫抑制。 然而，在所有猴中迅速产生了强烈的抗小鼠IG反应。 在本研究中，我们报告了一种成功的人源化形式的mu 5A 8（hu 5A 8），它保留了与人和猴CD 4的结合和抗艾滋病病毒活性。 当静脉内给予正常恒河猴时，hu 5A 8结合所有靶CD 4+细胞而不消耗，并且显示出比mu 5A 8显著更长的血浆半衰期。 然而，主要针对V区决定簇的抗hu 5A 8应答最终在大多数动物中在2至4周内出现。 然而，当将hu 5A 8给予慢性感染猕猴的猿免疫缺陷病毒的恒河猴时，未检测到抗hu 5A 8抗体。 在这些动物中重复施用hu 5A 8导致持续的血浆水平和用人源化抗体包被的CD 4+细胞持续六周。 这些研究证明了长期给予CD 4特异性mAb作为治疗或预防HIV-1感染的潜在手段的可行性。