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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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.
The authors declare no competing financial interests.
Extended data figures and tables
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.
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.
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).
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.
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).
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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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