A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties
A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties
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DOI：
10.1089/aid.1997.13.933
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发表时间：
1997-07-20
影响因子：
1.5
通讯作者：
Burkly, LC
中科院分区：
文献类型：
--
作者：
Reimann, KA;Lin, WY;Burkly, LC
针对CD 4的某些单克隆抗体（MAb）可以有效地阻断HIV-1在体外的复制。为了探索针对CD 4的被动免疫疗法用于预防或治疗艾滋病病毒感染，我们先前检测了非消耗性CD 4特异性鼠MAb mu 5A 8的生物学活性。该MAb特异于CD 4的结构域2，在gp 120-CD 4结合步骤后阻断HIV-1的复制，当给予正常恒河猴时，所有的CD 4（+）靶细胞都被抗体包被，但没有细胞清除或可测量的免疫抑制发生，然而，强烈的抗小鼠IG应答在所有猴中迅速发展。在本研究中，我们报道了成功的人源化形式的mu 5A 8（hu 5A 8），其保留了与人和猴CD 4的结合和抗AIDS病毒活性，当静脉内给予正常恒河猴时，hu 5A 8与所有靶CD 4（+）细胞结合而不消耗，并且显示出比mu 5A 8显著更长的血浆半衰期。然而，在大多数动物中，主要针对V区决定簇的抗hu 5AS应答最终在2至4周内出现。当将hu 5A 8给药于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 5AS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6周，这些研究证明了长期给予CD 4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 (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-hu5AS 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-hu5AS 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.