Antibody therapies for the prevention and treatment of viral infections

Salazar, Georgina; Zhang, Ningyan; Fu, Tong-Ming; An, Zhiqiang

n and AIDS. 77 A number of broadly HIV-1 neutralizing antibodies are currently in clinical development to assess their therapeutic benefit in passive immunization. Most of the HIV mAbs in clinical testing, for instance VRC01, 3BNC117, 10-1074, and 4E10, are broadly neutralizing on the basis of targeting conserved viral epitopes. 78 PRO 140 is an antibody used to treat HIV targeting host CCR5, which often acts with CD4 as a co-receptor for the virus. 79 Many excellent reviews provide more detail on broadly neutralizing antibodies against HIV. 77, [80] [81] [82] Here we highlight some examples of HIV targeting antibodies in clinical development. VRC01: VRC01 is a broadly neutralizing HIV-1 mAb isolated from the B cells of an HIV-infected patient. 40, 83 It is directed against the HIV-1 CD4-binding site and is capable of potently neutralizing diverse HIV-1 strains. 84 A Phase 1 study showed that the antibody was safe and demonstrated expected half-life and pharmacokinetics for a human IgG. 85 In two open-label trials of the safety, side-effect profile, pharmacokinetic properties, the antiviral activity of VRC01 was tested in persons with HIV infection who were undergoing ART (antiretroviral therapy) interruption. The antibody slightly delayed plasma viral rebound in the trial participants as compared with historical controls, but did not maintain viral suppression through week 8 86 VRC01 is being tested in multiple Phase 2 trials. [87] [88] [89] 3BNC117: Human antibody 3BNC117was isolated from single B cells of a patient with high titers of broadly neutralizing Antibody therapies for viral infections G Salazar et al. antibodies. This antibody binds to an HIV gp120 core glycoprotein stabilized in the CD4-bound conformation and lacking the variable (V) loops 1 to 3. 90 Antibody 3BNC117 blocked infection and suppressed viremia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. 91 In Phase 1 trial, 3BNC117 is safe and effective in reducing HIV-1 viremia. 92 In a Phase 2a trial, 3BNC117 suppresses viral rebound in humans during treatment interruption. The antibody exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans. 93 In addition to suppressing viremia in HIV-1-infected individuals, 3BNC117 can enhance host humoral immunity to HIV-1 94 . Antibody 3BNC117 is also being tested in combination with a functionally similar broadly neutralizing antibody, 10-1074, in the treatment of HIV-1 infection. 91, 95, 96 4E10, 2F5, and 2G12: Antibodies that recognize the highly conserved membrane proximal external region in the gp41 ectodomain stem of HIV such as 4E10, 2F5, and 2G12 have been tested in Phase 1/2 trials in well-suppressed HAART-treated individuals treated during acute and early HIV-1 infection. 97 Pro 140, Ibalizumab, and bispecific antibodies: In addition to antibodies directly targeting viral antigens to prevent and treat HIV-1 infection, antibodies targeting host receptors such as CCR5 and CD4 receptor are also being developed for HIV infection. For example, the CCR5 targeting humanized IgG4 mAb Pro 140 has been tested in clinical trials and the antibody exhibited potent, long-lived antiviral activity and was generally well tolerated. 79, 98, 99 Ibalizumab (iMab), a humanized mAb that binds to a conformational epitope on CD4