1932

Abstract

Broadly neutralizing antibodies (bNAbs) have been evaluated as promising agents in the fight against infectious diseases. HIV-1-specific bNAbs, in particular, have been tested in both preventive and therapeutic modalities. Multiple bNAbs have been isolated, characterized, and assessed in vitro and in vivo, but no single antibody appears to possess the breadth and potency that may be needed if it is to be used in the treatment of HIV-1 infection. With the technological advances of the past decades, novel and more effective bNAbs have been identified or engineered for higher neutralizing potency, greater breadth, and increased serum half-life. In this review, we discuss the development of a new generation of anti-HIV-1 bNAbs and their potential to be used clinically for treatment and prevention of HIV-1 infection.

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2018-01-29
2024-06-19
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Literature Cited

  1. Wang H, Wolock TM. 1. GBD 2015 HIV Collaborators, et al. 2016. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. Lancet HIV 3:e361–87 [Google Scholar]
  2. Mugo NR, Ngure K, Kiragu M. 2.  et al. 2016. The preexposure prophylaxis revolution; from clinical trials to programmatic implementation. Curr. Opin. HIV AIDS 11:80–86 [Google Scholar]
  3. Sultan B, Benn P, Waters L. 3.  2014. Current perspectives in HIV post-exposure prophylaxis. HIV/AIDS 6:147–58 [Google Scholar]
  4. Levy J, Youvan T, Lee ML. 4.  1994. Passive hyperimmune plasma therapy in the treatment of acquired immunodeficiency syndrome: results of a 12-month multicenter double-blind controlled trial. The Passive Hyperimmune Therapy Study Group. Blood 84:2130–35 [Google Scholar]
  5. Karpas A, Gray J, Byron N. 5.  et al. 1990. Passive immunization in ARC and AIDS. Biotherapy 2:159–72 [Google Scholar]
  6. Vittecoq D, Mattlinger B, Barre-Sinoussi F. 6.  et al. 1992. Passive immunotherapy in AIDS: a randomized trial of serial human immunodeficiency virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. J. Infect. Dis. 165:364–68 [Google Scholar]
  7. Jackson GG, Perkins JT, Rubenis M. 7.  et al. 1988. Passive immunoneutralization of human immunodeficiency virus in patients with advanced AIDS. Lancet 2:647–52 [Google Scholar]
  8. Kovacs JA, Baseler M, Dewar RJ. 8.  et al. 1995. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N. Engl. J. Med. 332:567–75 [Google Scholar]
  9. Koenig S, Conley AJ, Brewah YA. 9.  et al. 1995. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat. Med. 1:330–36 [Google Scholar]
  10. Karpas A, Gillson W, Bevan PC, Oates JK. 10.  1985. Lytic infection by British AIDS virus and development of rapid cell test for antiviral antibodies. Lancet 2:695–97 [Google Scholar]
  11. Mascola JR, Louwagie J, McCutchan FE. 11.  et al. 1994. Two antigenically distinct subtypes of human immunodeficiency virus type 1: viral genotype predicts neutralization serotype. J. Infect. Dis. 169:48–54 [Google Scholar]
  12. Pilgrim AK, Pantaleo G, Cohen OJ. 12.  et al. 1997. Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection. J. Infect. Dis. 176:924–32 [Google Scholar]
  13. Richman DD, Wrin T, Little SJ, Petropoulos CJ. 13.  2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. PNAS 100:4144–49 [Google Scholar]
  14. Burton DR, Pyati J, Koduri R. 14.  et al. 1994. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266:1024–27 [Google Scholar]
  15. Muster T, Steindl F, Purtscher M. 15.  et al. 1993. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J. Virol. 67:6642–47 [Google Scholar]
  16. Trkola A, Pomales AB, Yuan H. 16.  et al. 1995. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J. Virol. 69:6609–17 [Google Scholar]
  17. Barbas CF, Björling E, Chiodi F. 17.  et al. 1992. Recombinant human Fab fragments neutralize human type 1 immunodeficiency virus in vitro. PNAS 89:9339–43 [Google Scholar]
  18. Li A, Baba T, Sodroski J. 18.  et al. 1997. Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations. AIDS Res. Hum. Retrovir. 13:647–56 [Google Scholar]
  19. Roben P, Moore J, Thali M. 19.  et al. 1994. Recognition properties of a panel of human recombinant Fab fragments to the CD4. J. Virol. 68:4821–28 [Google Scholar]
  20. Trkola A, Purtscher M, Muster T. 20.  et al. 1996. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70:1100–8 [Google Scholar]
  21. Chen Y, Dierich M. 21.  1996. Identification of a second site in HIV-1 gp41 mediating binding to cells. Immunol. Lett. 52:153–56 [Google Scholar]
  22. Li D, Liu J, Zhang L. 22.  et al. 2015. N-terminal residues of an HIV-1 gp41 membrane-proximal external region antigen influence broadly neutralizing 2F5-like antibodies. Virol. Sin. 30:449–56 [Google Scholar]
  23. Zwick M, Labrijn A, Wang M. 23.  et al. 2001. Broadly neutralizing antibodies targeted to the membrane-proximal external region. J. Virol. 75:10892–905 [Google Scholar]
  24. Pinter A, Honnen WJ, Kayman SC. 24.  et al. 1998. Potent neutralization of primary HIV-1 isolates by antibodies directed against epitopes present in the V1/V2 domain of HIV-1 gp120. Vaccine 16:1803–11 [Google Scholar]
  25. Karwowska S, Gorny MK, Buchbinder A. 25.  et al. 1992. Production of human monoclonal antibodies specific for conformational and linear non-V3 epitopes of gp120. AIDS Res. Hum. Retrovir. 8:1099–106 [Google Scholar]
  26. Zolla-Pazner S. 26.  2004. Identifying epitopes of HIV-1 that induce protective antibodies. Nat. Rev. Immunol. 4:199–210 [Google Scholar]
  27. Mascola JR, Lewis MG, Stiegler G. 27.  et al. 1999. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol. 73:4009–18 [Google Scholar]
  28. Xu W, Hofmann-Lehmann R, McClure H, Ruprecht R. 28.  2002. Passive immunization with human neutralizing monoclonal antibodies: correlates of protective immunity against HIV. Vaccine 20:1956–60 [Google Scholar]
  29. Mascola JR, Stiegler G, VanCott TC. 29.  et al. 2000. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6:207–10 [Google Scholar]
  30. Baba T, Liska V, Hofmann-Lehmann R. 30.  et al. 2000. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6:200–6 [Google Scholar]
  31. Ruprecht R, Hofmann-Lehmann R, Smith-Franklin B. 31.  et al. 2001. Protection of neonatal macaques against experimental SHIV infection by human neutralizing monoclonal antibodies. Transfus. Clin. Biol. 8:350–58 [Google Scholar]
  32. Stiehm E, Fletcher C, Mofenson L. 32.  et al. 2000. Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273). J. Infect. Dis. 181:548–54 [Google Scholar]
  33. Trkola A, Kuster H, Rusert P. 33.  et al. 2005. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat. Med. 11:615–22 [Google Scholar]
  34. Tiller T, Meffre E, Yurasov S. 34.  et al. 2008. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329:112–24 [Google Scholar]
  35. Scheid JF, Mouquet H, Feldhahn N. 35.  et al. 2009. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458:636–40 [Google Scholar]
  36. Wu X, Yang ZY, Li Y. 36.  et al. 2010. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329:856–61 [Google Scholar]
  37. West AP Jr., Diskin R, Nussenzweig MC, Bjorkman PJ. 37.  2012. Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120. PNAS 109:E2083–90 [Google Scholar]
  38. Wu X, Zhou T, Zhu J. 38.  et al. 2011. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333:1593–602 [Google Scholar]
  39. Shingai M, Nishimura Y, Klein F. 39.  et al. 2013. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503:277–80 [Google Scholar]
  40. Barouch DH, Whitney JB, Moldt B. 40.  et al. 2013. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503:224–28 [Google Scholar]
  41. Klein F, Halper-Stromberg A, Horwitz JA. 41.  et al. 2012. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492:118–22 [Google Scholar]
  42. Pegu A, Yang ZY, Boyington JC. 42.  et al. 2014. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci. Trans. Med. 6:243ra88 [Google Scholar]
  43. Lynch RM, Boritz E, Coates EE. 43.  et al. 2015. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Trans. Med. 7:319ra206 [Google Scholar]
  44. Caskey M, Klein F, Lorenzi JC. 44.  et al. 2015. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522:487–91 [Google Scholar]
  45. Bar KJ, Sneller MC, Harrison LJ. 45.  et al. 2016. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N. Engl. J. Med. 375:2037–50 [Google Scholar]
  46. Scheid JF, Horwitz JA, Bar-On Y. 46.  et al. 2016. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535:556–60 [Google Scholar]
  47. Gray GE, Laher F, Lazarus E. 47.  et al. 2016. Approaches to preventative and therapeutic HIV vaccines. Curr. Opin. Virol. 17:104–9 [Google Scholar]
  48. Walker LM, Phogat SK, Chan-Hui PY. 48.  et al. 2009. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326:285–89 [Google Scholar]
  49. Walker LM, Huber M, Doores KJ. 49.  et al. 2011. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477:466–70 [Google Scholar]
  50. Bonsignori M, Hwang KK, Chen X. 50.  et al. 2011. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J. Virol. 85:9998–10009 [Google Scholar]
  51. Doria-Rose NA, Schramm CA, Gorman J. 51.  et al. 2014. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509:55–62 [Google Scholar]
  52. Saunders KO, Nicely NI, Wiehe K. 52.  et al. 2017. Vaccine elicitation of high mannose-dependent neutralizing antibodies against the V3-glycan broadly neutralizing epitope in nonhuman primates. Cell Rep 18:2175–88 [Google Scholar]
  53. Mouquet H, Scharf L, Euler Z. 53.  et al. 2012. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. PNAS 109:E3268–77 [Google Scholar]
  54. Huang J, Ofek G, Laub L. 54.  et al. 2012. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491:406–12 [Google Scholar]
  55. Falkowska E, Le KM, Ramos A. 55.  et al. 2014. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40:657–68 [Google Scholar]
  56. Scharf L, Scheid JF, Lee JH. 56.  et al. 2014. Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7:785–95 [Google Scholar]
  57. Huang J, Kang BH, Pancera M. 57.  et al. 2014. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface. Nature 515:138–42 [Google Scholar]
  58. Caskey M, Schoofs T, Gruell H. 58.  et al. 2017. Antibody 10–1074 suppresses viremia in HIV-1-infected individuals. Nat. Med. 23:185–91 [Google Scholar]
  59. Lippow SM, Wittrup KD, Tidor B. 59.  2007. Computational design of antibody-affinity improvement beyond in vivo maturation. Nat. Biotechnol. 25:1171–76 [Google Scholar]
  60. Igawa T, Tsunoda H, Kuramochi T. 60.  et al. 2011. Engineering the variable region of therapeutic IgG antibodies. mAbs 3:243–52 [Google Scholar]
  61. Diskin R, Scheid JF, Marcovecchio PM. 61.  et al. 2011. Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334:1289–93 [Google Scholar]
  62. Rudicell RS, Kwon YD, Ko SY. 62.  et al. 2014. Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J. Virol. 88:12669–82 [Google Scholar]
  63. Pancera M, Shahzad-Ul-Hussan S, Doria-Rose NA. 63.  et al. 2013. Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16. Nat. Struct. Mol. Biol. 20:804–13 [Google Scholar]
  64. Kong R, Louder MK, Wagh K. 64.  et al. 2015. Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes. J. Virol. 89:2659–71 [Google Scholar]
  65. Gautam R, Nishimura Y, Pegu A. 65.  et al. 2016. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105–9 [Google Scholar]
  66. Chames P, Baty D. 66.  2009. Bispecific antibodies for cancer therapy. Curr. Opin. Drug Discov. Dev. 12:276–83 [Google Scholar]
  67. Sun M, Pace CS, Yao X. 67.  et al. 2014. Rational design and characterization of the novel, broad and potent bispecific HIV-1 neutralizing antibody iMabm36. J. Acquir. Immune Defic. Syndr. 66:473–83 [Google Scholar]
  68. Huang Y, Yu J, Lanzi A. 68.  et al. 2016. Engineered bispecific antibodies with exquisite HIV-1-neutralizing activity. Cell 165:1621–31 [Google Scholar]
  69. Asokan M, Rudicell RS, Louder M. 69.  et al. 2015. Bispecific antibodies targeting different epitopes on the HIV-1 envelope exhibit broad and potent neutralization. J. Virol. 89:12501–12 [Google Scholar]
  70. Zalevsky J, Chamberlain AK, Horton HM. 70.  et al. 2010. Enhanced antibody half-life improves in vivo activity. Nat. Biotechnol. 28:157–59 [Google Scholar]
  71. Hinton PR, Johlfs MG, Xiong JM. 71.  et al. 2004. Engineered human IgG antibodies with longer serum half-lives in primates. J. Biol. Chem. 279:6213–16 [Google Scholar]
  72. Robbie GJ, Criste R, Dall'acqua WF. 72.  et al. 2013. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob. Agents Chemother. 57:6147–53 [Google Scholar]
  73. Dall'Acqua WF, Woods RM, Ward ES. 73.  et al. 2002. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J. Immunol. 169:5171–80 [Google Scholar]
  74. Datta-Mannan A, Witcher DR, Tang Y. 74.  et al. 2007. Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. J. Biol. Chem. 282:1709–17 [Google Scholar]
  75. Ko SY, Pegu A, Rudicell RS. 75.  et al. 2014. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514:642–45 [Google Scholar]
  76. Pandey JP, Li Z. 76.  2013. The forgotten tale of immunoglobulin allotypes in cancer risk and treatment. Exp. Hematol. Oncol. 2:6 [Google Scholar]
  77. Vidarsson G, Dekkers G, Rispens T. 77.  2014. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5:520 [Google Scholar]
  78. Pandey JP. 78.  2014. Genetic variants of Fcγ (GM allotypes) and the Fc-mediated effector functions in HIV-1 controllers. J. Virol. 88:7117 [Google Scholar]
  79. Fudenberg HH, Franklin EC. 79.  1964. The hereditary human gamma globulin (GM) groups and the structural subunits of human gamma-globulin. Bibl. Haematol. 19:483–90 [Google Scholar]
  80. Jefferis R, Lefranc MP. 80.  2009. Human immunoglobulin allotypes: possible implications for immunogenicity. mAbs 1:332–38 [Google Scholar]
  81. Zhu C, Lee V, Finn A. 81.  et al. 2012. Origin of immunoglobulin isotype switching. Curr. Biol. 22:872–80 [Google Scholar]
  82. Bartelds GM, de Groot E, Nurmohamed MT. 82.  et al. 2010. Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study. Arthritis Res. Ther. 12:R221 [Google Scholar]
  83. Magdelaine-Beuzelin C, Vermeire S, Goodall M. 83.  et al. 2009. IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab. Pharmacogenetics Genom 19:383–87 [Google Scholar]
  84. Rojko JL, Evans MG, Price SA. 84.  et al. 2014. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies. Toxicol. Pathol. 42:725–64 [Google Scholar]
  85. Euler Z, Alter G. 85.  2015. Exploring the potential of monoclonal antibody therapeutics for HIV-1 eradication. AIDS Res. Hum. Retrovir. 31:13–24 [Google Scholar]
  86. Mazor Y, Yang C, Borrok MJ. 86.  et al. 2016. Enhancement of immune effector functions by modulating IgG's intrinsic affinity for target antigen. PLOS ONE 11:e0157788 [Google Scholar]
  87. Eryilmaz E, Janda A, Kim J. 87.  et al. 2013. Global structures of IgG isotypes expressing identical variable regions. Mol. Immunol. 56:588–98 [Google Scholar]
  88. Schoch A, Kettenberger H, Mundigl O. 88.  et al. 2015. Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. PNAS 112:5997–6002 [Google Scholar]
  89. Wang W, Lu P, Fang Y. 89.  et al. 2011. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metab. Dispos. 39:1469–77 [Google Scholar]
  90. Rader C. 90.  2011. DARTs take aim at BiTEs. Blood 117:4403–4 [Google Scholar]
  91. Sung JA, Pickeral J, Liu L. 91.  et al. 2015. Dual-affinity re-targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells. J. Clin. Investig. 125:4077–90 [Google Scholar]
  92. Sloan DD, Lam CY, Irrinki A. 92.  et al. 2015. Targeting HIV reservoir in infected CD4 T cells by dual-affinity re-targeting molecules (DARTs) that bind HIV envelope and recruit cytotoxic T cells. PLOS Pathog 11:e1005233 [Google Scholar]
  93. Wong R, Pepper C, Brennan P. 93.  et al. 2013. Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica 98:1930–38 [Google Scholar]
  94. Pegu A, Asokan M, Wu L. 94.  et al. 2015. Activation and lysis of human CD4 cells latently infected with HIV-1. Nat. Commun. 6:8447 [Google Scholar]
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