Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study
Yehuda Z Cohen, Allison L Butler, Katrina Millard, Maggi Witmer-Pack, Rebeka Levin, Cecilia Unson-O'Brien, Roshni Patel, Irina Shimeliovich, Julio C C Lorenzi, Jill Horowitz, Stephen R Walsh, Shu Lin, Joshua A Weiner, Anna Tse, Alicia Sato, Chelsey Bennett, Bryan Mayer, Kelly E Seaton, Nicole L Yates, Lindsey R Baden, Allan C deCamp, Margaret E Ackerman, Michael S Seaman, Georgia D Tomaras, Michel C Nussenzweig, Marina Caskey, Yehuda Z Cohen, Allison L Butler, Katrina Millard, Maggi Witmer-Pack, Rebeka Levin, Cecilia Unson-O'Brien, Roshni Patel, Irina Shimeliovich, Julio C C Lorenzi, Jill Horowitz, Stephen R Walsh, Shu Lin, Joshua A Weiner, Anna Tse, Alicia Sato, Chelsey Bennett, Bryan Mayer, Kelly E Seaton, Nicole L Yates, Lindsey R Baden, Allan C deCamp, Margaret E Ackerman, Michael S Seaman, Georgia D Tomaras, Michel C Nussenzweig, Marina Caskey
Abstract
Background: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults.
Methods: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536.
Findings: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics.
Interpretation: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.
Conflict of interest statement
I have read the journal’s policy and the authors of this manuscript have the following competing interests: There are patents on 3BNC117 (US Provisional Application No. 61/715,642) and 10-1074 (US Provisional Application No. 61/486,960) on which MCN is an inventor. The authors declare no further conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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References
- Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–99. Epub 2010/11/26. 10.1056/NEJMoa1011205
- Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410. Epub 2012/07/13. 10.1056/NEJMoa1108524
- Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423–34. Epub 2012/07/13. 10.1056/NEJMoa1110711 .
- McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387(10013):53–60. Epub 2015/09/14. 10.1016/S0140-6736(15)00056-2
- Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509–18. Epub 2015/02/05. 10.1056/NEJMoa1402269
- Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–22. Epub 2012/07/13. 10.1056/NEJMoa1202614
- van der Straten A, Stadler J, Luecke E, Laborde N, Hartmann M, Montgomery ET, et al. Perspectives on use of oral and vaginal antiretrovirals for HIV prevention: the VOICE-C qualitative study in Johannesburg, South Africa. J Int AIDS Soc. 2014;17(3 Suppl 2):19146 Epub 2014/09/17. 10.7448/IAS.17.3.19146
- Siedner MJ, Hettema A, Hughey A, Oldenburg CE, Kohler S, Barnighausen K, et al. Preference for injectable over oral HIV pre-exposure prophylaxis in public-sector primary-care clinics in Swaziland. AIDS. 2018;32(11):1541–2. Epub 2018/05/26. 10.1097/QAD.0000000000001859 .
- Cohen YZ, Caskey M. Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. Curr Opin HIV AIDS. 2018;13(4):366–73. Epub 2018/04/27. 10.1097/COH.0000000000000475 .
- Mouquet H, Scharf L, Euler Z, Liu Y, Eden C, Scheid JF, et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A. 2012;109(47):E3268–77. 10.1073/pnas.1217207109
- Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, Oliveira TY, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011;333(6049):1633–7. 10.1126/science.1207227
- Kong R, Louder MK, Wagh K, Bailer RT, deCamp A, Greene K, et al. Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes. J Virol. 2015;89(5):2659–71. Epub 2014/12/19. 10.1128/JVI.03136-14
- Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature. 2012;492(7427):118–22. Epub 2012/10/30. 10.1038/nature11604
- Shingai M, Nishimura Y, Klein F, Mouquet H, Donau OK, Plishka R, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature. 2013;503(7475):277–80. Epub 2013/11/01. 10.1038/nature12746
- Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, Eisenreich TR, et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A. 2013;110(41):16538–43. Epub 2013/09/18. 10.1073/pnas.1315295110
- Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr., Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–91. 10.1038/nature14411
- Caskey M, Schoofs T, Gruell H, Settler A, Karagounis T, Kreider EF, et al. Antibody 10–1074 suppresses viremia in HIV-1-infected individuals. Nat Med. 2017;23(2):185–91. 10.1038/nm.4268 .
- Bar-On Y, Gruell H, Schoofs T, Pai JA, Nogueira L, Butler AL, et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat Med. 2018. Epub 2018/09/28. 10.1038/s41591-018-0186-4 .
- Mendoza P, Gruell H, Nogueira L, Pai JA, Butler AL, Millard K, et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. 2018;561(7724):479–84. Epub 2018/09/28. 10.1038/s41586-018-0531-2
- Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature. 2016;533(7601):105–9. Epub 2016/04/28. 10.1038/nature17677
- Gautam R, Nishimura Y, Gaughan N, Gazumyan A, Schoofs T, Buckler-White A, et al. A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med. 2018;24(5):610–6. Epub 2018/04/18. 10.1038/s41591-018-0001-2
- Sarzotti-Kelsoe M, Bailer RT, Turk E, Lin CL, Bilska M, Greene KM, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods. 2014;409:131–46. Epub 2013/12/03. 10.1016/j.jim.2013.11.022
- Huang Y, Zhang L, Ledgerwood J, Grunenberg N, Bailer R, Isaacs A, et al. Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults. MAbs. 2017;9(5):792–800. Epub 2017/04/04. 10.1080/19420862.2017.1311435
- Davda JP, Dodds MG, Gibbs MA, Wisdom W, Gibbs J. A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design. MAbs. 2014;6(4):1094–102. Epub 2014/05/20. 10.4161/mabs.29095
- Abdool Karim Q, Baxter C, Birx D. Prevention of HIV in Adolescent Girls and Young Women: Key to an AIDS-Free Generation. J Acquir Immune Defic Syndr. 2017;75 Suppl 1:S17–S26. Epub 2017/04/12. 10.1097/QAI.0000000000001316 .
- Mendoza P, Gruell H, Nogueira L, Butler AL, Millard K, Lehmann C, et al. Combination therapy with anti-HIV-1 antibodies 3BNC117 and 10–1074 maintains viral suppression during treatment interruption. Nature. In press.
- Gaudinski MR, Coates EE, Houser KV, Chen GL, Yamshchikov G, Saunders JG, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018;15(1):e1002493 Epub 2018/01/25. 10.1371/journal.pmed.1002493 .
- Mayer KH, Seaton KE, Huang Y, Grunenberg N, Isaacs A, Allen M, et al. Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial. PLoS Med. 2017;14(11):e1002435 Epub 2017/11/15. 10.1371/journal.pmed.1002435
- Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010;28(2):157–9. Epub 2010/01/19. 10.1038/nbt.1601
- Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, Nabel GJ, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med. 2014;211(10):2061–74. Epub 2014/08/27. 10.1084/jem.20132494
- Fenyo EM, Heath A, Dispinseri S, Holmes H, Lusso P, Zolla-Pazner S, et al. International network for comparison of HIV neutralization assays: the NeutNet report. PLoS One. 2009;4(2):e4505 Epub 2009/02/21. 10.1371/journal.pone.0004505
- Heyndrickx L, Heath A, Sheik-Khalil E, Alcami J, Bongertz V, Jansson M, et al. International network for comparison of HIV neutralization assays: the NeutNet report II. PLoS One. 2012;7(5):e36438 Epub 2012/05/17. 10.1371/journal.pone.0036438
- Provine NM, Cortez V, Chohan V, Overbaugh J. The neutralization sensitivity of viruses representing human immunodeficiency virus type 1 variants of diverse subtypes from early in infection is dependent on producer cell, as well as characteristics of the specific antibody and envelope variant. Virology. 2012;427(1):25–33. Epub 2012/03/01. 10.1016/j.virol.2012.02.001
- Cohen YZ, Lorenzi JCC, Seaman MS, Nogueira L, Schoofs T, Krassnig L, et al. Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Clade B Clinical Isolates Produced in Peripheral Blood Mononuclear Cells. J Virol. 2018;92(5). Epub 2017/12/15. 10.1128/JVI.01883-17
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