Reimann K A, Lin W, Bixler S, Browning B, Ehrenfels B N, Lucci J, Miatkowski K, Olson D, Parish T H, Rosa M D, Oleson F B, Hsu Y M, Padlan E A, Letvin N L, Burkly L C
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
AIDS Res Hum Retroviruses. 1997 Jul 20;13(11):933-43. doi: 10.1089/aid.1997.13.933.
Certain monoclonal antibodies (MAbs) 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 2 to 4 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 6 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CD4的单克隆抗体（MAb）在体外能有效阻断HIV-1复制。为探索针对CD4的被动免疫疗法用于预防或治疗艾滋病病毒感染，我们之前检测了一种非耗竭性CD4特异性鼠源单克隆抗体mu5A8的生物学活性。这种针对CD4第2结构域的单克隆抗体在gp120与CD4结合后的步骤阻断HIV-1复制。当给正常恒河猴注射时，所有CD4+靶细胞都被抗体包被，但未发生细胞清除或可检测到的免疫抑制。然而，所有猴子都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人源化的mu5A8（hu5A8），它保留了与人和猴CD4的结合以及抗艾滋病病毒活性。当静脉注射给正常恒河猴时，hu5A8能与所有靶CD4+细胞结合而不导致细胞耗竭，并且其血浆半衰期比mu5A8显著延长。尽管如此，在大多数动物中，一种主要针对V区决定簇的抗hu5A8反应最终在2至4周内出现。然而，当将hu5A8注射给慢性感染猕猴猿猴免疫缺陷病毒的恒河猴时，未检测到抗hu5A8抗体。在这些动物中重复注射hu5A8导致血浆水平持续升高，并且人源化抗体包被CD4+细胞达6周之久。这些研究证明了长期注射CD4特异性单克隆抗体作为治疗或预防HIV-1感染潜在手段的可行性。
