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

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

doi:10.1038/nature14411

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

Nature. 2015 Jun 25;522(7557):487-91. doi: 10.1038/nature14411. Epub 2015 Apr 8.

Authors

Marina Caskey¹, Florian Klein¹, Julio C C Lorenzi¹, Michael S Seaman², Anthony P West Jr³, Noreen Buckley¹, Gisela Kremer⁴, Lilian Nogueira¹, Malte Braunschweig⁵, Johannes F Scheid¹, Joshua A Horwitz¹, Irina Shimeliovich¹, Sivan Ben-Avraham¹, Maggi Witmer-Pack¹, Martin Platten⁶, Clara Lehmann⁶, Leah A Burke⁷, Thomas Hawthorne⁸, Robert J Gorelick⁹, Bruce D Walker¹⁰, Tibor Keler⁸, Roy M Gulick¹¹, Gerd Fätkenheuer⁶, Sarah J Schlesinger¹, Michel C Nussenzweig¹²

Affiliations

¹ Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
² Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
³ Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
⁴ 1] First Department of Internal Medicine, University Hospital of Cologne, D-50924 Cologne, Germany [2] Clinical Trials Center Cologne, ZKS Köln, BMBF 01KN1106, University of Cologne, Cologne, Germany.
⁵ 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Albert Ludwigs University of Freiburg, 79085 Freiburg, Germany.
⁶ 1] First Department of Internal Medicine, University Hospital of Cologne, D-50924 Cologne, Germany [2] German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.
⁷ 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Division of Infectious Diseases, Weill Medical College of Cornell University, New York, New York 10065, USA.
⁸ Celldex Therapeutics, Inc., Hampton, New Jersey 08827, USA.
⁹ AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
¹⁰ Ragon Institute of MGH, MIT and Harvard, Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA.
¹¹ Division of Infectious Diseases, Weill Medical College of Cornell University, New York, New York 10065, USA.
¹² 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.

Abstract

HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. 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. 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, 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 log10 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.

Publication types

Clinical Trial, Phase I
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amino Acid Sequence
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
Binding Sites
Broadly Neutralizing Antibodies
CD4 Antigens / metabolism
Case-Control Studies
Evolution, Molecular
Female
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 / immunology
HIV Infections / therapy*
HIV Infections / virology
HIV-1 / chemistry
HIV-1 / drug effects
HIV-1 / immunology*
Humans
Immunization, Passive / methods
Male
Middle Aged
Molecular Sequence Data
Time Factors
Viral Load / drug effects
Viral Load / immunology*
Viremia / immunology
Viremia / therapy*
Viremia / virology
Young Adult

Substances

3BNC117 antibody
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antibodies, Neutralizing
Broadly Neutralizing Antibodies
CD4 Antigens
HIV Antibodies
HIV Envelope Protein gp120

Abstract

Publication types

MeSH terms

Substances

Grants and funding