Journal Article

Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117

Nogueira, Lilian, Witmer-Pack, Maggi, Kremer, Gisela, West, Anthony P., Platten, Martin, Scheid, Johannes F., Braunschweig, Malte, Caskey, Marina, Walker, Bruce D., Shimeliovich, Irina, Hawthorne, Thomas, Buckley, Noreen, Keler, Tibor, Horwitz, Joshua A., Klein, Florian, Nussenzweig, Michel C., Gorelick, Robert J., Ben-Avraham, Sivan, Fätkenheuer, Gerd, Gulick, Roy M., Seaman, Michael S., Lehmann, Clara, Lorenzi, Julio C. C., Schlesinger, Sarah J., Burke, Leah A.

2015

Overview

A phase I study of passive immunization with a CD4 binding-site-directed broadly neutralizing antibody shows that it transiently reduces HIV-1 viral loads in humans. Anti-HIV antibody shows promise The passive administration of broadly neutralizing antibodies (bNAbs) to HIV has been effective against HIV-1 infection in humanized mice and macaque models of HIV-1 infection. It has been suggested that bNAbs, administered passively or by viral vectors, may be effective for prevention and immunotherapy in humans. The safety and efficacy of the approach had not been tested in humans previously but here Michel Nussenzweig and colleagues report the results of a phase I study of passive immunization with neutralizing antibodies directed at CD4 binding sites, and show that the treatment transiently reduces HIV viral loads in humans. HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned 1 , 2 , 3 . However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4 , 5 ). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated 6 , 7 , 8 , 9 , 10 . Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody 11 , in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg −1 infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8–2.5 log 10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/255/1901 / Adult / Amino Acid Sequence / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Monoclonal - therapeutic use / Antibodies, Monoclonal, Humanized / Antibodies, Neutralizing - administration & dosage / Antibodies, Neutralizing - adverse effects / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - pharmacology / Antibodies, Neutralizing - therapeutic use / Antigens / Binding Sites / Broadly Neutralizing Antibodies / Case-Control Studies / CD4 Antigens - metabolism / Cloning / Drug dosages / Evolution, Molecular / Female / HIV / HIV Antibodies - administration & dosage / HIV Antibodies - adverse effects / HIV Antibodies - immunology / HIV Antibodies - pharmacology / HIV Antibodies - therapeutic use / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - immunology / HIV infections / HIV Infections - immunology / HIV Infections - therapy / HIV Infections - virology / HIV-1 - chemistry / HIV-1 - drug effects / HIV-1 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immune system / Immunization, Passive - methods / Immunoglobulins / Immunotherapy / Infections / letter / Male / Middle Aged / Molecular Sequence Data / multidisciplinary / Pharmacokinetics / Physiological aspects / Science / Time Factors / Viral Load - drug effects / Viral Load - immunology / Viremia - immunology / Viremia - therapy / Viremia - virology / Virus diseases / Young Adult