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Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals

Nature Medicine volume 24, pages 1701–1707 (2018)Cite this article

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Abstract

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7,8,9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10,11,12. Here we report on a phase 1b clinical trial (NCT02825797) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg−1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

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Fig. 1: Study design and pharmacokinetics of 3BNC117 and 10-1074 in HIV-1-infected individuals.
Fig. 2: Viral load following 3BNC117/10-1074 infusions in HIV-1-infected participants.
Fig. 3: Phylogenetic sequence analysis of viremic participants.
Fig. 4: HIV-1 escape analysis of individuals receiving 3BNC117 and 10-1074 therapy.

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Data availability

All requests for raw and analyzed data and materials are promptly reviewed by the Rockefeller University to verify whether the request is subject to any intellectual property or confidentiality obligations. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a Material Transfer Agreement. HIV-1 envelope SGA data are available in GenBank, accession numbers MH632763–MH633255.

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Acknowledgements

We thank all study participants who devoted time to our research; members of the Klein and Nussenzweig laboratories for helpful discussions, especially P. Mendoza, C.-L. Lu, J. C. C. Lorenzi, L. Cohn and M. Jankovic; R. Levin, G. Kremer and D. Weiland for study coordination; the Rockefeller University Hospital Clinical Research Support Office and nursing staff as well as C. Golder, E. Thomas, M. Platten, S. Margane and T. Kümmerle for help with recruitment and study implementation; C. Ruping and M. Schlotz for help with sample processing; S. Kiss for ophthalmologic assessments; T. Keler and the Celldex Therapeutics team for 3BNC117 and 10-1074 manufacturing and regulatory support; C. Conrad for regulatory support; U. Kerkweg for pharmaceutical services; H. Janicki, M. Ercanoglu, P. Schommers and R. Kaiser for help with virus cultures; P. Fast and H. Park for clinical monitoring; S. McMillan, S. Mosher, S. Sawant, D. Beaumont, M. Sarzotti-Kelsoe, K. Greene, H. Gao and D. Montefiori for help with PK assay development, validation, reporting and/or project management; and S. Schlesinger for input on study design. This work was supported by The Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1092074, OPP1124068 (M.C.N.), CAVIMC OPP1146996 (G.D.T., M.S.S.); the NIH grants 1UM1 AI100663 and R01AI-129795 (M.C.N.); the Heisenberg-Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961) and the German Center for Infection Research (DZIF) (F.K.); the Einstein-Rockefeller-CUNY Center for AIDS Research (1P30AI124414-01A1); BEAT-HIV Delaney grant UM1 AI126620 (M.C.); and the Robertson fund. M.C.N. is a Howard Hughes Medical Institute Investigator.

Author information

Author notes

  1. These authors contributed equally: Yotam Bar-On, Henning Gruell.

  2. These authors jointly supervised this work: Marina Caskey, Florian Klein, Michel C. Nussenzweig.

Authors and Affiliations

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

    Yotam Bar-On, Till Schoofs, Joy A. Pai, Lilian Nogueira, Allison L. Butler, Katrina Millard, Thiago Y. Oliveira, Theodora Karagounis, Yehuda Z. Cohen, Shiraz Belblidia, Juan P. Dizon, Maggi Witmer-Pack, Irina Shimeliovich, Jill Horowitz, Marina Caskey & Michel C. Nussenzweig

  2. Laboratory of Experimental Immunology, Institute of Virology, University Hospital Cologne, Cologne, Germany

    Henning Gruell, Till Schoofs, Kanika Jain & Florian Klein

  3. Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany

    Henning Gruell, Clara Lehmann, Isabelle Suárez, Christoph Wyen, Jörg J. Vehreschild, Kerstin Fiddike & Gerd Fätkenheuer

  4. German Center for Infection Research, Partner Site Bonn–Cologne, Cologne, Germany

    Henning Gruell, Clara Lehmann, Isabelle Suárez, Jörg J. Vehreschild, Gerd Fätkenheuer & Florian Klein

  5. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    Clara Lehmann, Isabelle Suárez & Florian Klein

  6. Praxis am Ebertplatz, Cologne, Germany

    Christoph Wyen

  7. Praxis Hohenstaufenring, Cologne, Germany

    Stefan Scholten

  8. Methods in Medical Informatics, Department of Computer Science, University of Tübingen, Tübingen, Germany

    Lisa Handl & Nico Pfeifer

  9. Duke Human Vaccine Institute, Duke University, Durham, NC, USA

    Kelly E. Seaton, Nicole L. Yates & Georgia D. Tomaras

  10. Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA

    Roy M. Gulick

  11. Medical Faculty, University of Tübingen, Tübingen, Germany

    Nico Pfeifer

  12. German Center for Infection Research, Partner Site Tübingen, Tübingen, Germany

    Nico Pfeifer

  13. Max Planck Institute for Informatics, Saarbrücken, Germany

    Nico Pfeifer

  14. Departments of Surgery, Immunology and Molecular Genetics and Microbiology, Duke University, Durham, NC, USA

    Georgia D. Tomaras

  15. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Michael S. Seaman

  16. Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

    Michel C. Nussenzweig

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Contributions

M.C. (principal investigator in the United States), F.K. (principal investigator in Germany) and M.C.N. designed the trial; Y.B.-O., H.G., M.C., F.K. and M.C.N. analyzed the data and wrote the manuscript; Y.B.-O., T.S. and T.K. performed single-genome sequencing; H.G., A.L.B., K.M., M.W.-P., K.F., J.H., M.C. and F.K. implemented the study; Y.Z.C., R.M.G. and G.F. contributed to study design and implementation; C.L., I.Su., C.W. and S.S. contributed to participant recruitment and clinical assessments; J.A.P. and T.Y.O. performed bioinformatics processing; H.G., L.N. and T.K. performed viral cultures; L.H. and N.P. contributed to statistical analyses; S.B., J.P.D., J.J.V., I.Sh. and K.J. performed, coordinated or contributed to sample processing; K.E.S., N.L.Y. and G.D.T. performed anti-idiotypic ELISAs; and M.S.S. performed neutralization assays.

Corresponding authors

Correspondence to Marina Caskey, Florian Klein or Michel C. Nussenzweig.

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Competing interests

There are patents on 3BNC117 and 10-1074 on which M.C.N. is an inventor.

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Bar-On, Y., Gruell, H., Schoofs, T. et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat Med 24, 1701–1707 (2018). https://doi.org/10.1038/s41591-018-0186-4

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