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Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

Abstract

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

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Figure 1: Study design and pharmacokinetics of 10-1074 in HIV-1-negative participants and individuals with HIV-1 infection.
Figure 2: Viral load dynamics after 10-1074 infusion in participants with HIV-1.
Figure 3: Viral evolution after 10-1074 infusion in participants with HIV-1 infection.
Figure 4: Temporal evolution of escape from 10-1074 over time in individuals 1HB1, 1HB3, 1HC1, 1HD1, 1HD6K and 1HD10K.
Figure 5: SMRT sequencing analysis.

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Acknowledgements

We thank all study participants for devoting their time to support our research. We thank the Clinical Research Support Teams of the Rockefeller University Hospital and the Infectious Disease Division at the University Hospital Cologne, in particular, C. Golder, G. Kremer, S. Margane and E. Thomas. We thank L. Burke, S. Durant, M. Platten,I. Suárez and the nursing staff for patient care and recruitment, and all members of the laboratories of M.C.N. and F.K. for helpful discussions. We thank P. Fast and H. Park for clinical monitoring, A. Louie, D. Jordan, C. Conrad and D. Adzic for regulatory support, C. Anthony and S. Zhou for help in establishing Primer-ID sequencing, C. Ruping, K. Jain, M. Ercanoglu, R. Patel and J. Dizon for sample processing, U. Kerkweg, R. Macarthur and A. Johnson for pharmacy services, A. Germann and H. von Briesen for HIV culture analyses, R. Kaiser for p24 measurements and D. Sok for providing PGT121 and PGDM1400 for neutralization assays. Amplification and library preparation for SMRT sequencing was performed with the support of the Translational Virology Core at the UC San Diego Center for AIDS Research (P30 AI036214). SMRT sequencing was conducted at the IGM Genomics Center, University of California, San Diego, La Jolla, California. Computational analysis of sequence data was performed, in part, on a cluster, which was supported by U01 GM110749 (NIH/NIGMS). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1032144 (M.S.S.), OPP1092074 and OPP1124068 (M.C.N.), National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (P.J.B.), a BEAT-HIV Delaney grant UM1 AI126620 (B.H.H.), the Robertson Foundation to M.C.N., and the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.). T.S. was supported by a German Research Foundation postdoctoral fellowship (SCHO 1612/1-1) and is currently supported in part by grant #UL1 TR001866 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. H.G. is supported by a fellowship from the German Center for Infection Research (DZIF). T. Karagounis is an HHMI Medical Research Fellow. E.F.K. is supported by a Ruth L. Kirschstein National Research Service Award (F30 AI112426). B.M. was supported by grant number R00 AI120851 from the National Institute of Allergy and Infectious Diseases. K.E. was supported by T15 LM007092 from the National Library of Medicine. F.K. is supported by the Heisenberg Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961) and the German Center for Infection Research (DZIF), partner site Bonn–Cologne, Cologne, Germany. M.C.N. is a Howard Hughes Medical Institute Investigator. Aspects of this work are encompassed by patent application PCT/US2013/065696.

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Contributions

M.C. (principal investigator, US), M.C.N. and F.K. (principal investigator, Germany) designed the trial; M.C., T.S., H.G., M.C.N. and F.K. analyzed the data and wrote the manuscript; R.M.G., G.F. and S.J.S. contributed to study design and implementation. M.C., H.G., A.S., Y.Z.C., R.L., M.W.-P. and F.K. implemented the study. C.L., D.G., T. Kümmerle., C.W., S.K., B.S.Z. and G.F. contributed to participant recruitment and clinical assessments. I.S., C.U.-O. and D.W. coordinated sample processing. T.S., T. Karagounis and L.N., performed viral culture, SGS and Primer-ID sequencing work. T.Y.O. performed Primer-ID analyses and bioinformatics processing of SGS data. A.R. and M.S.S. performed TZM.bl neutralization assays. B.M., K.E. and C.I. carried out SMRT sequencing and analysis. E.F.K., G.H.L. and B.H.H. analyzed SGS data. N.P. performed statistical analysis. H.M., A.P.W. and P.J.B. contributed to data analysis. T. Keler was responsible for 10-1074 manufacture and provided regulatory guidance. All authors read and contributed to the writing of the manuscript.

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

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Competing interests

T. Keler is employed by Celldex Therapeutics. 10-1074 was manufactured by Celldex Therapeutics.

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Caskey, M., Schoofs, T., Gruell, H. et al. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med 23, 185–191 (2017). https://doi.org/10.1038/nm.4268

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