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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Klein, F. et al. Antibodies in HIV-1 vaccine development and therapy. Science 341, 1199–1204 (2013).
Hraber, P. et al. Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. AIDS 28, 163–169 (2014).
West, A.P. Jr. et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156, 633–648 (2014).
Mikell, I. et al. Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog. 7, e1001251 (2011).
Burton, D.R. & Mascola, J.R. Antibody responses to envelope glycoproteins in HIV-1 infection. Nat. Immunol. 16, 571–576 (2015).
Haynes, B.F. et al. HIV-host interactions: implications for vaccine design. Cell Host Microbe 19, 292–303 (2016).
Moore, P.L., Williamson, C. & Morris, L. Virological features associated with the development of broadly neutralizing antibodies to HIV-1. Trends Microbiol. 23, 204–211 (2015).
Buchacher, A. et al. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res. Hum. Retroviruses 10, 359–369 (1994).
Muster, T. et al. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J. Virol. 67, 6642–6647 (1993).
Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012).
Mouquet, H. et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc. Natl. Acad. Sci. USA 109, E3268–E3277 (2012).
Walker, L.M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).
Sok, D. et al. Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci. Transl. Med. 6, 236ra63 (2014).
Garces, F. et al. Structural evolution of glycan recognition by a family of potent HIV antibodies. Cell 159, 69–79 (2014).
Walker, L.M. et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009).
Sok, D. et al. Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proc. Natl. Acad. Sci. USA 111, 17624–17629 (2014).
Scheid, J.F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).
Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010).
Liao, H.X. et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469–476 (2013).
Scharf, L. et al. Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep. 7, 785–795 (2014).
Huang, J. et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature 515, 138–142 (2014).
Pietzsch, J. et al. A mouse model for HIV-1 entry. Proc. Natl. Acad. Sci. USA 109, 15859–15864 (2012).
Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 109, 18921–18925 (2012).
Gautam, R. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016).
Shingai, M. et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J. Exp. Med. 211, 2061–2074 (2014).
Klein, F. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122 (2012).
Horwitz, J.A. et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc. Natl. Acad. Sci. USA 110, 16538–16543 (2013).
Barouch, D.H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013).
Shingai, M. et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277–280 (2013).
Halper-Stromberg, A. et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158, 989–999 (2014).
Hessell, A.J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014).
Lu, C.L. et al. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352, 1001–1004 (2016).
Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).
Lynch, R.M. et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206 (2015).
Ledgerwood, J.E. et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin. Exp. Immunol. 182, 289–301 (2015).
Schoofs, T. et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 352, 997–1001 (2016).
Scheid, J.F. et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556–560 (2016).
Yoon, H. et al. CATNAP: a tool to compile, analyze and tally neutralizing antibody panels. Nucleic Acids Res. 43, W213–W219 (2015).
Li, M. et al. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 79, 10108–10125 (2005).
Seaman, M.S. et al. Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J. Virol. 84, 1439–1452 (2010).
Sarzotti-Kelsoe, M. et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J. Immunol. Methods 409, 131–146 (2014).
Keizer, R.J., Huitema, A.D., Schellens, J.H. & Beijnen, J.H. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49, 493–507 (2010).
Moir, S. & Fauci, A.S. B cells in HIV infection and disease. Nat. Rev. Immunol. 9, 235–245 (2009).
Gristick, H.B. et al. Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat. Struct. Mol. Biol. 23, 906–915 (2016).
Abram, M.E., Ferris, A.L., Shao, W., Alvord, W.G. & Hughes, S.H. Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J. Virol. 84, 9864–9878 (2010).
Coffin, J.M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267, 483–489 (1995).
Maldarelli, F. et al. HIV populations are large and accumulate high genetic diversity in a nonlinear fashion. J. Virol. 87, 10313–10323 (2013).
Zhou, S., Jones, C., Mieczkowski, P. & Swanstrom, R. Primer ID validates template sampling depth and greatly reduces the error rate of next-generation sequencing of HIV-1 genomic RNA populations. J. Virol. 89, 8540–8555 (2015).
Bhiman, J.N. et al. Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies. Nat. Med. 21, 1332–1336 (2015).
Laird Smith, M. et al. Rapid Sequencing of Complete env Genes from Primary HIV-1 Samples. in Virus Evolution (Oxford University Press, 2016).
Bar, K.J. et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N. Engl. J. Med. 375, 2037–2050 (2016).
Lynch, R.M. et al. HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies. J. Virol. 89, 4201–4213 (2015).
West, A.P. Jr. et al. Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues. Proc. Natl. Acad. Sci. USA 110, 10598–10603 (2013).
Trkola, A. et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat. Med. 11, 615–622 (2005).
Simek, M.D. et al. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J. Virol. 83, 7337–7348 (2009).
Ratcliffe, S.J. & Shults, J. GEEQBOX: A MATLAB toolbox for generalized estimating equations and quasi-least squares. J. Stat. Softw. 25, 1–14 (2008).
Salazar-Gonzalez, J.F. et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J. Virol. 82, 3952–3970 (2008).
Larkin, M.A. et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).
Guindon, S. et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst. Biol. 59, 307–321 (2010).
Darriba, D., Taboada, G.L., Doallo, R. & Posada, D. jModelTest 2: more models, new heuristics and parallel computing. Nat. Methods 9, 772 (2012).
Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30, 1312–1313 (2014).
Kirchherr, J.L. et al. High throughput functional analysis of HIV-1 env genes without cloning. J. Virol. Methods 143, 104–111 (2007).
Keele, B.F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl. Acad. Sci. USA 105, 7552–7557 (2008).
Katoh, K. & Standley, D.M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol. Biol. Evol. 30, 772–780 (2013).
Price, M.N., Dehal, P.S. & Arkin, A.P. FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS One 5, e9490 (2010).
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.
T. Keler is employed by Celldex Therapeutics. 10-1074 was manufactured by Celldex Therapeutics.
About this article
Cite this article
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
Adenosine deaminase-1 enhances germinal center formation and functional antibody responses to HIV-1 Envelope DNA and protein vaccines
Aerosol Delivery of Synthetic mRNA to Vaginal Mucosa Leads to Durable Expression of Broadly Neutralizing Antibodies against HIV
Molecular Therapy (2020)
Combination therapies currently under investigation in phase I and phase II clinical trials for HIV-1
Expert Opinion on Investigational Drugs (2020)
A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies