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  • A Corrigendum to this article was published on 23 March 2016

Abstract

HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned1,2,3. 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 evaluated6,7,8,9,10. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody11, 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.

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Acknowledgements

We thank all individuals who participated in this study. We thank the Rockefeller University Hospital Clinical Research Support Office and nursing staff, as well as T. Kümmerle, C. Wyen, and L. Siegel for help with recruitment; S. Kiss for ophthalmologic assessments; F. Maldarelli and J. Lifson for single-copy analysis and B. Freemire for technical assistance; J. Pring, A. Almaktari, C. Unsen, S. Hadrigan, E. Thomas, H. Gruell, D. Gillor, and U. Sandaradura de Silva for sample processing and study coordination, and N. Rodziewicz for help with HIV-1 culturing. We thank A. Louie and C. Conrad for help with regulatory submissions; L. Thomas for IND-enabling studies, L. Vitale for cell line and anti-idiotype antibody development, B. Riordan, A. Rayo and J. Andreozzi for anti-idiotype ELISA method development and sample analysis, R. Hammond for process development, and S. DiSciullo for 3BNC117 manufacturing; J. Perry for performing neutralization assays. We thank M. Suarez-Farinas for support with statistical analysis; P. Fast and H. Park for clinical monitoring; and E. Gotschlich and B. Coller for input on study design. J.C.C.L. is supported by an award from CNPq “Ciencia sem Fronteiras” Brazil (248676/2013-0). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1033115 (M.C.N.), OPP1092074 (M.C.N.), OPP1040753 (A.P.W.) and OPP1032144 (M.S.S.), by grant #UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), by a grant from the Robertson Foundation to M.C.N., in part with Federal funds from the NCI/NIH, under Contract No. HHSN261200800001E, and a grant from the German Center for Infection Research (DZIF) to G.F. 3BNC117 was generated from a subject in the International HIV Controller Study, supported by the Mark and Lisa Schwartz Foundation and CAVD Grant 43307. M.C.N. and B.D.W. are Howard Hughes Medical Institute Investigators. The authors declare no competing financial interests.

Author information

Author notes

    • Marina Caskey
    •  & Florian Klein

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA

    • Marina Caskey
    • , Florian Klein
    • , Julio C. C. Lorenzi
    • , Noreen Buckley
    • , Lilian Nogueira
    • , Malte Braunschweig
    • , Johannes F. Scheid
    • , Joshua A. Horwitz
    • , Irina Shimeliovich
    • , Sivan Ben-Avraham
    • , Maggi Witmer-Pack
    • , Leah A. Burke
    • , Sarah J. Schlesinger
    •  & Michel C. Nussenzweig
  2. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Michael S. Seaman
  3. Division of Biology, California Institute of Technology, Pasadena, California 91125, USA

    • Anthony P. West Jr
  4. First Department of Internal Medicine, University Hospital of Cologne, D-50924 Cologne, Germany

    • Gisela Kremer
    • , Martin Platten
    • , Clara Lehmann
    •  & Gerd Fätkenheuer
  5. Clinical Trials Center Cologne, ZKS Köln, BMBF 01KN1106, University of Cologne, Cologne, Germany

    • Gisela Kremer
  6. Albert Ludwigs University of Freiburg, 79085 Freiburg, Germany

    • Malte Braunschweig
  7. German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany

    • Martin Platten
    • , Clara Lehmann
    •  & Gerd Fätkenheuer
  8. Division of Infectious Diseases, Weill Medical College of Cornell University, New York, New York 10065, USA

    • Leah A. Burke
    •  & Roy M. Gulick
  9. Celldex Therapeutics, Inc., Hampton, New Jersey 08827, USA

    • Thomas Hawthorne
    •  & Tibor Keler
  10. AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA

    • Robert J. Gorelick
  11. Ragon Institute of MGH, MIT and Harvard, Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA

    • Bruce D. Walker
  12. Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA

    • Michel C. Nussenzweig

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Contributions

M.C. and F.K. planned and implemented the study, analysed the data, and wrote the manuscript; J.C.C.L. performed sequence analyses, and contributed to writing the manuscript; M.S.S. performed TZM.bl neutralization assays; A.P.W. assisted with sequence analyses; N.B., G.K., S.B.-A., M.W.-P., M.P., L.A.B. implemented the study; L.N. and M.B. performed cloning and sequencing; I.S., C.L. coordinated sample processing; T.H. performed ELISA assays; and R.J.G. performed single copy assays. T.K. was responsible for 3BNC117 manufacture and provided regulatory guidance; J.F.S., B.D.W., J.A.H. contributed to study design and helped with the manuscript; R.M.G. contributed to study design; and G.F. and S.J.S. contributed to study design and implementation. M.C.N. planned and implemented the study, analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michel C. Nussenzweig.

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    Supplementary Figures

    This file contains Supplementary Figure 1, which shows the HIV-1 envelope sequence analysis.

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https://doi.org/10.1038/nature14411

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