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

Nature volume 522, pages 487–491 (2015)Cite this article

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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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Figure 1: Pharmacokinetics of 3BNC117 in uninfected and HIV-1-infected individuals.
Figure 2: HIV-1 viral load measurements.
Figure 3: 3BNC117 sensitivity, changes in viraemia, and 3BNC117 levels.
Figure 4: HIV-1 envelope sequence analysis after 3BNC117 infusion.

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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

  1. Marina Caskey and Florian Klein: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10065, New York, 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, 02215, Massachusetts, USA

    Michael S. Seaman

  3. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Anthony P. West Jr

  4. First Department of Internal Medicine, University Hospital of Cologne, Cologne, D-50924, 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, Freiburg, 79085, 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, 10065, New York, USA

    Leah A. Burke & Roy M. Gulick

  9. Celldex Therapeutics, Inc., Hampton, 08827, New Jersey, USA

    Thomas Hawthorne & Tibor Keler

  10. AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick, Frederick National Laboratory for Cancer Research, Frederick, 21702, Maryland, USA

    Robert J. Gorelick

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

    Bruce D. Walker

  12. Howard Hughes Medical Institute, The Rockefeller University, New York, 10065, New York, USA

    Michel C. Nussenzweig

Authors
  1. Marina Caskey
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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.

Corresponding author

Correspondence to Michel C. Nussenzweig.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 HIV-1 neutralizing activity of 3BNC117.

a, Summary of 3BNC117 neutralizing in vitro activity based on 237 HIV-1 isolates comprising 6 different clades. Data were retrieved from the ‘AntibodyDatabase’ by A.P.W. (ref. 39). b, Illustration of the fraction (that is, % coverage; y axis) of HIV-1 isolates that are neutralized at a given IC50 (μg ml−1; x axis) using the same data set.

Extended Data Figure 2 CD4+ and CD8+ T-cell counts before and after 3BNC117 infusion.

a, Absolute numbers (cells μl−1) of CD4+ and CD8+ T-cell counts of all enrolled HIV-1-infected participants at screen, on the day of 3BNC117 infusion (day 0), and at day 28 after infusion. b, Percentage of CD4+ and CD8+ T cells for the same subjects and time points. Mean and standard deviation are indicated in red and black, respectively. No significant differences between pre-infusion and post infusion levels were detected by using one-way ANOVA.

Extended Data Figure 3 3BNC117 serum concentration and activity in single subjects.

a, b, Serum levels of 3BNC117 in all uninfected (a) and HIV-1-infected (b) individuals that received 1, 3, 10, or 30 mg kg−1 3BNC117 at day 0. Antibody levels were measured by a sandwich ELISA using an anti-3BNC117 specific antibody (green) or by measuring the 3BNC117 serum activity in a TZM.bl neutralization assay (blue).

Extended Data Figure 4 3BNC117 sensitivity and changes in viraemia in 2 ART-treated subjects.

Both subjects were on ART when enrolled in the study and received a single dose (2B2, 3 mg kg−1; 2C2, 10 mg kg−1) of 3BNC117 at day 0. The left y axis shows log10 change in viraemia from baseline, and right y axis shows antibody level measured in ELISA. Blue line reflects change in VL and dotted grey line antibody level. Numbers indicate IC50 values for 3BNC117 of autologous viral isolates measured by TZM.bl assay, colour-coded as indicated on the right.

Extended Data Figure 5 Correlating viral decay with 3BNC117 sensitivity and starting viral load.

a, Maximum decline in viral load in ART-untreated HIV-1-infected participants with baseline 3BNC117-sensitive viruses (IC50 < 1 μg ml−1) versus pre-treatment (day 0) viral load (Pearson coefficient r = 0.72 P = 0.03; Spearman coefficient rho = 0.78, P = 0.02). b, Maximum drop in viral load in HIV-1-infected and viremic individuals receiving a 10 or 30 mg kg−1 dose of 3BNC117 (y axis) versus baseline autologous virus sensitivity to 3BNC117 (x axis; Pearson coefficient r = 0.69 P = 0.03; Spearman coefficient rho = 0.41, P = 0.23).

Extended Data Table 1 Baseline characteristics of HIV-1-infected individuals and 3BNC117 safety data
Full size table
Extended Data Table 2 HIV-1 RNA levels and viral decay mixed-effect linear model
Full size table
Extended Data Table 3 Sensitivity of autologous virus isolates and cloned HIV-1 envelopes to 3BNC117
Full size table
Extended Data Table 4 Pharmacokinetics of 3BNC117 based on a 56-day period post infusion
Full size table
Extended Data Table 5 Summary of 3BNC117 pharmacokinetics based on a 56-day period post infusion
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This file contains Supplementary Figure 1, which shows the HIV-1 envelope sequence analysis. (PDF 382 kb)

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Caskey, M., Klein, F., Lorenzi, J. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015). https://doi.org/10.1038/nature14411

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