ANTI CD4 BASED THERAPIES FOR HIV INFECTION

某些针对CD4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cd4导向的被动免疫疗法预防或治疗艾滋病病毒感染，我们之前检测了一种非耗竭的cd4特异性小鼠单克隆抗体mu5A8的生物活性。这种针对CD4结构域2的单抗可在gp120/CD4结合后阻断HIV-1的复制。当给药给正常恒河猴时，所有CD4+靶细胞都被抗体包裹，但没有细胞清除或可测量的免疫抑制发生。然而，所有猴子都迅速产生了强烈的抗小鼠Ig反应。在目前的研究中，我们报道了一种成功的人源化的mu5A8 (hu5A8)，它保留了与人类和猴子CD4的结合和抗艾滋病病毒的活性。当静脉注射给正常恒河猴时，hu5A8与所有目标CD4+细胞结合而不耗尽，并且显示出比mu5A8更长的血浆半衰期。然而，在大多数动物中，主要针对V区决定因子的抗hu5a8反应最终在两到四周内出现。然而，当长期感染猴免疫缺陷病毒的恒河猴注射hu5A8时，未检测到抗hu5A8抗体。在这些动物中反复给药hu5A8可使血浆水平和CD4+细胞被人源化抗体包膜维持6周。这些研究证明了慢性给药cd4特异性单克隆抗体作为治疗或预防HIV-1感染的潜在手段的可行性。

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.