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

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.