Abstract
Passive immunization has been used since the late 1800’s to prevent and treat human infectious diseases. Administration of animal immune sera and human immunoglobulin has given way to the use of monoclonal antibodies (mAbs) for passive immunization, and highly potent broadly neutralizing anti-HIV antibodies (bNAbs) are now being considered for HIV therapy and prophylaxis. Recent studies have shown that systemic and topical administration of bNAbs can effectively inhibit HIV/SHIV mucosal transmission in macaques and in humanized mice, and selected bNAbs are currently being tested in clinical trials for safety and efficacy in humans.
In this review, we outline strategies for the selection, engineering and manufacture of human bNAbs to prevent the sexual transmission of HIV, describe the proof-of-concept animal studies that have demonstrated mAb-mediated protection against mucosal HIV transmission, and review clinical trials currently underway to test the safety and efficacy of mAb-based HIV prevention in humans.
Keywords: HIV, passive immunization, broadly neutralizing antibodies, monoclonal antibodies, sexual transmission, HIV.
[1]
Hey A. History and Practice: Antibodies in infectious diseases. Microbiol Spectr 2015; 3: AID-0026-.
[2]
Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495-7.
[3]
McCafferty J, Griffiths AD, Winter G, Chiswell DJ. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 1990; 348(6301): 552-4.
[4]
Steinitz M, Kelin G, Koskimies S, Makel O. EB virus-induced B lymphocyte cell lines producing specific antibody. Nature 1977; 269(5627): 420-2.
[5]
Tiller T, Meffre E, Yurasov S, et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 2008; 329(1-2): 112-24.
[6]
Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. MAbs 2015; 7(1): 9-14.
[7]
Zeitlin L, Whaley KJ, Olinger GG, et al. Antibody therapeutics for Ebola virus disease. Curr Opin Virol 2016; 17: 45-9.
[8]
Patel HD, Nikitin P, Gesner T, et al. In vitro characterization of human cytomegalovirus-targeting therapeutic monoclonal antibodies LJP538 and LJP539. Antimicrob Agents Chemother 2016; 60(8): 4961-71.
[9]
Prince AM, Reesink H, Pascual D, et al. Prevention of HIV infection by passive immunization with HIV immunoglobulin. AIDS Res Hum Retroviruses 1991; 7(12): 971-3.
[10]
Putkonen P, Thorstensson R, Ghavamzadeh L, et al. Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys. Nature 1991; 352(6334): 436-8.
[11]
Shibata R, Igarashi T, Haigwood N, et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat Med 1999; 5(2): 204-10.
[12]
Van Rompay KK, Berardi CJ, Dillard-Telm S, et al. Passive immunization of newborn rhesus macaques prevents oral simian immunodeficiency virus infection. J Infect Dis 1998; 177(5): 1247-59.
[13]
Burton DR, Barbas CF III, Persson MA, et al. A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc Natl Acad Sci USA 1991; 88(22): 10134-7.
[14]
Walker LM, Phogat SK, Chan-Hui PY, et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 2009; 326(5950): 285-9.
[15]
Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep 2016; 13(1): 31-7.
[16]
Burton DR, Hessell AJ, Keele BF, et al. Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci USA 2011; 108(27): 11181-6.
[17]
Hessell AJ, Poignard P, Hunter M, et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat Med 2009; 15(8): 951-4.
[18]
Hessell AJ, Rakasz EG, Poignard P, et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog 2009; 5(5): e1000433.
[19]
Mascola JR, Stiegler G, VanCott TC, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 2000; 6(2): 207-10.
[20]
Nishimura Y, Igarashi T, Haigwood N, et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J Virol 2002; 76(5): 2123-30.
[21]
Parren PW, Marx PA, Hessell AJ, et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol 2001; 75(17): 8340-7.
[22]
Veazey RS, Shattock RJ, Pope M, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 2003; 9(3): 343-6.
[23]
Willey R, Nason MC, Nishimura Y, et al. Neutralizing antibody titers conferring protection to macaques from a simian/human immunodeficiency virus challenge using the TZM-bl assay. AIDS Res Hum Retroviruses 2010; 26(1): 89-98.
[24]
Moog C, Dereuddre-Bosquet N, Tellaud JL, et al. Protective effect of vaginal application of neutralizing and nonneutralizing inhibitory antibodies against vaginal SHIV challenge in macaques. Mucosal Immunol 2014; 7(1): 46-56.
[25]
Deruaz M, Moldt B, Le KM, et al. Protection of humanized mice from repeated intravaginal HIV challenge by passive immunization: A model for studying the efficacy of neutralizing antibodies in vivo. J Infect Dis 2016; 214(4): 612-6.
[26]
Luo XM, Lei MYYY, Feidi RA, et al. Dimeric 2G12 as a potent protection against HIV-1. PLoS Pathog 2010; 6(12): e1001225.
[27]
Stoddart CA, Galkina SA, Joshi P, et al. Efficacy of broadly neutralizing monoclonal antibody PG16 in HIV-infected humanized mice. Virology 2014; 462-463: 115-25.
[28]
Sun M, Li Y, Yuan Z, et al. VRC01 antibody protects against vaginal and rectal transmission of human immunodeficiency virus 1 in hu-BLT mice. Arch Virol 2016; 161(9): 2449-55.
[29]
Veselinovic M, Neff CP, Mulder LR, et al. Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model. Virology 2012; 432(2): 505-10.
[30]
Caskey M, Lorenzi JC, Seaman MS, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 2015; 522(7557): 487-91.
[31]
Ledgerwood JE, Coates EE, Yamshchikov G, et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol 2015; 182(3): 289-301.
[32]
Hessell AJ, Hangartner L, Hunter M, et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 2007; 449(7158): 101-4.
[33]
Hessell AJ, Rakasz EG, Tehrani DM, et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol 2010; 84(3): 1302-13.
[34]
Klein K, Veazey RS, Warrier R, et al. Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge. J Virol 2013; 87(21): 11604-16.
[35]
Moldt B, Shibata-Koyama M, Rakasz EG, et al. A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced Fcγ RIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. J Virol 2012; 86(11): 6189-96.
[36]
McCoy LE, Burton DR. Identification and specificity of broadly neutralizing antibodies against HIV. Immunol Rev 2017; 275(1): 11-20.
[37]
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361(23): 2209-20.
[38]
Anderson DJ. Modeling mucosal cell-associated HIV type 1 transmission in vitro. J Infect Dis 2014; 210(Suppl. 3): S648-53.
[39]
Anderson DJ, Politch JA, Nadolski AM, Blaskewicz CD, Pudney J, Mayer KH. Targeting trojan horse leukocytes for HIV prevention. AIDS 2010; 24(2): 163-87.
[40]
Sattentau Q. Avoiding the void: Cell-to-cell spread of human viruses. Nat Rev Microbiol 2008; 6(11): 815-26.
[41]
Zhong P, Agosto LM. Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV. PLoS One 2013; 8(1): e53138.
[42]
Politch JA, Marathe J, Anderson DJ. Characteristics and quantities of HIV host cells in human genital tract secretions. J Infect Dis 2014; 210(Suppl. 3): S609-15.
[44]
Delacroix DL, Hodgson HJ, McPherson A, et al. Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva. J Clin Invest 1982; 70(2): 230-41.
[45]
Bakema JE, van Egmond M. The human immunoglobulin A Fc receptor FcαRI: A1 multifaceted regulator of mucosal immunity. Mucosal Immunol 2011; 4(6): 612-24.
[46]
Husband AJ, Gowans JL. The origin and antigen-dependent distribution of IgA-containing cells in the intestine. J Exp Med 1978; 148(5): 1146-60.
[49]
Phalipon A, Corthésy B. Novel functions of the polymeric Ig receptor: Well beyond transport of immunoglobulins. Trends Immunol 2003; 24(2): 55-8.
[50]
Brandtzaeg P. Secretory IgA: Designed for anti-microbial defense. Front Immunol 2013; 4(222): 1-17.
[51]
Virdi V, Juarez P, Boudolf V, Depicker A. Recombinant IgA production for mucosal passive immunization, advancing beyond the hurdles. Cell Mol Life Sci 2016; 73(3): 535-45.
[52]
Ma JK, Lehnerr T, Stabila P, Fux CI, Hiatt A. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med 1998; 4(5): 601-6.
[53]
Yu X, Duval M, Lewis C, et al. Impact of IgA constant domain on HIV-1 neutralizing function of monoclonal antibody F425A1g8. J Immunol 2013; 190(1): 205-10.
[54]
Watkins JD, Sholukh AM, Mukhtar MM, et al. Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS 2013; 27(9): F13-20.
[55]
Huang YT, Wright A, Gao X, Kulick L, Yan H, Lamm ME. Intraepithelial cell neutralization of HIV-1 replication by IgA. J Immunol 2005; 174(8): 4828-35.
[56]
Hur EM, Patel SN, Shimizu S, et al. Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood 2012; 120(23): 4571-82.
[57]
Stieh D, King DF, Klein K, et al. Aggregate complexes of HIV-1 induced by multimeric antibodies. Retrovirology 2014; 11(1): 78-94.
[58]
Bonner A, Furtado PB, Almogren A, Kerr MA, Perkins SJ. Implications of the near-planar solution structure of human myeloma dimeric IgA1 for mucosal immunity and IgA nephropathy. J Immunol 2008; 180(2): 1008-18.
[59]
Wright A, Lamm ME, Huang YT. Excretion of human immunodeficiency virus type 1 through polarized epithelium by immunoglobulin A. J Virol 2008; 82(23): 11526-35.
[60]
Fouda GG, Eudailey J, Kunz EL, et al. Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization. Mucosal Immunol 2017; 10(1): 228-37.
[61]
Huang Y, Yu J, Lanzi A, et al. Engineered bispecific antibodies with exquisite HIV-1-neutralizing activity. Cell 2016; 165(7): 1621-31.
[62]
Chiang JJ, Gardner MR, Quinlan BD, Dorfman T, Choe H, Farzan M. Enhanced recognition and neutralization of HIV-1 by antibody-derived CCR5-mimetic peptide variants. J Virol 2012; 86(22): 12417-21.
[63]
Galimidi RP, Klein JS, Politzer MS, et al. Intra-spike crosslinking overcomes antibody evasion by HIV-1. Cell 2015; 160(3): 433-46.
[64]
Kumar R, Tuen M, Liu J, et al. Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines. Vaccine 2013; 31(46): 5413-21.
[65]
Lu L, Chen Y, Xiong W, et al. F(ab’)2 fragment of a gp41 NHR-trimer-induced IgM monoclonal antibody neutralizes HIV-1 infection and blocks viral fusion by targeting the conserved gp41 pocket. Microbes Infect 2013; 15(13): 887-94.
[66]
Tran K, Poulsen C, Guenaga J, et al. Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign. Proc Natl Acad Sci USA 2014; 111(7): E738-47.
[67]
Yu Q, Yu R, Qin X. The good and evil of complement activation in HIV-1 infection. Cell Mol Immunol 2010; 7(5): 334-40.
[68]
Ahmad A, Menezes J. Antibody-dependent cellular cytotoxicity in HIV infections. FASEB J 1996; 10(2): 258-66.
[69]
Fanger MW, Shen L, Graziano RF, Guyre PM. Cytotoxicity mediated by human Fc receptors for IgG. Immunol Today 1989; 10(3): 92-9.
[70]
Klein JS, Webster A, Gnanapragasam PN, Galimidi RP, Bjorkman PJ. A dimeric form of the HIV-1 antibody 2G12 elicits potent antibody-dependent cellular cytotoxicity. AIDS 2010; 24(11): 1633-40.
[71]
Mabondzo A, Boussin FD, Raoul H, Dormont D. Antibody-dependent cellular cytotoxicity and neutralization of human immunodeficiency virus type 1 by high affinity cross-linking of gp41 to human macrophage Fc IgG receptor using bispecific antibody. J Gen Virol 1994; 75(6): 1451-6.
[72]
Perez LG, Costa MR, Todd CA, Haynes BF, Montefiori DC. Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: A specific role for antibodies against the membrane-proximal external region of gp41. J Virol 2009; 83(15): 7397-410.
[73]
Ackerman ME, Dugast A-S, McAndrew EG, et al. Enhanced phagocytic activity of HIV-specific antibodies correlates with natural production of immunoglobulins with skewed affinity for FcγR2a and FcγR2b. J Virol 2013; 87(10): 5468-76.
[74]
Dugast A-S, Tonelli A, Berger CT, et al. Decreased Fc receptor expression on innate immune cells is associated with impaired antibody-mediated cellular phagocytic activity in chronically HIV-1 infected individuals. Virology 2011; 415(2): 160-7.
[75]
Ahmed AA, Keremane SR, Vielmetter J, Bjorkman PJ. Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcgammaRIIIa. J Struct Biol 2016; 194(1): 78-89.
[76]
Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcɣ RIII and antibody-dependent cellular toxicity. J Biochem 2002; 277(30): 26733-40.
[77]
Ackerman ME, Crispin M, Yu X, et al. Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J Clin Invest 2013; 123(5): 2183-92.
[78]
Gunn BM, Schneider JR, Shansab M, et al. Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. Mucosal Immunol 2016; 9: 1549-58.
[79]
Cheeseman HM, Carias AM, Evans AB, et al. Expression profile of human Fc receptors in mucosal tissue: Implications for antibody-dependent cellular effector functions targeting HIV-1 transmission. PLoS One 2016; 11(5): e0154656.
[80]
Hussain LA, Kelly CG, Fellowes R, et al. Expression and gene transcript of Fc receptors for IgG, HLA class II antigens and Langerhans cells in human cervico-vaginal epithelium. Clin Exp Immunol 1992; 90(3): 530-8.
[81]
Hussain LA, Kelly CG, Hecht EM, Fellowes R, Jourdan M, Lehner T. The expression of Fc receptors for immunoglobulin G in human rectal epithelium. AIDS 1991; 5(9): 1089-94.
[82]
Albanesi M, Mancardi DA, Jonsson F, et al. Neutrophils mediate antibody-induced antitumor effects in mice. Blood 2013; 122(18): 3160-4.
[83]
Lu CL, Murakowski DK, Boumazos S, et al. Enhanced clearance of HIV-1–infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 2016; 352(6288): 1001-4.
[84]
Gómez-Román VR, Patterson LJ, Venzon D, et al. Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J Immunol 2005; 174(4): 2185-9.
[85]
Borrok MJ, Luheshi NM, Beyaz N, et al. Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding. MAbs 2015; 7(4): 743-51.
[86]
Roopenian DC, Akilesh S. FcRn: The neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7(9): 715-25.
[87]
Lu L, Palaniyandi S, Zeng R, et al. A neonatal Fc receptor-targeted mucosal vaccine strategy effectively induces HIV-1 antigen-specific immunity to genital infection. J Virol 2011; 85(20): 10542-53.
[88]
Euler Z, Alter G. Exploring the potential of monoclonal antibody therapeutics for HIV-1 eradication. AIDS Res Hum Retroviruses 2015; 31(1): 13-24.
[89]
Gong R, Wang Y, Ying T, et al. Bispecific engineered antibody domains (nanoantibodies) that interact noncompetitively with an HIV-1 neutralizing epitope and FcRn. PLoS One 2012; 7(8): e42288.
[90]
Ko W-Y, Pegu A, Rudicell RS, et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 2014; 514(7524): 642-5.
[91]
Kunert R, Reinhart D. Advances in recombinant antibody manufacturing. Appl Microbiol Biotechnol 2016; 100(8): 3451-61.
[92]
Dumont J, Euwart D, Mei B, Estes S, Kshirsagar R. Human cell lines for biopharmaceutical manufacturing: History, status, and future perspectives. Crit Rev Biotechnol 2015; 36(6): 1110-22.
[93]
Chapman SN, Mehndiratta P, Johansen MC, McMurry TL, Johnston KC, Southerland AM. Current perspectives on the use of intravenous recombinant tissue Plasminogen Activator (tPA) for treatment of acute ischemic stroke. Vasc Health Risk Manag 2014; 10: 75-87.
[94]
Hossler P, Khattak SF, Li ZJ. Optimal and consistent protein glycosylation in mammalian cell culture. Glycobiology 2009; 19(9): 936-49.
[95]
Spadiut O, Capone S, Krainer F, Glieder A, Herwig C. Microbials for the production of monoclonal antibodies and antibody fragments. Trends Biotechnol 2014; 32(1): 54-60.
[96]
Wurm FM. Production of recombinant protein therapeutics in cultivated mammalian cells. Nat Biotechnol 2004; 22(11): 1393-8.
[97]
de StGroth SF, Scheidegger D. Production of monoclonal antibodies: strategy and tactics. J Immunol Methods 1980; 35(1-2): 1-21.
[98]
Khan SU, Schroder M. Engineering of chaperone systems and of the unfolded protein response. Cytotechnology 2008; 57(3): 207-31.
[99]
Randall TD, Parkhouse RM, Corley RB. J chain synthesis and secretion of hexameric IgM is differentially regulated by lipopolysaccharide and interleukin 5. Proc Natl Acad Sci USA 1992; 89(3): 962-6.
[101]
Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 2012; 481(7379): 81-4.
[102]
Balazs AB, Ouyang Y, Hong CM, et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med 2014; 20(3): 296-300.
[103]
Saunders KO, Wang L, Joyce MG, et al. Broadly neutralizing human immunodeficiency virus type 1 antibody gene transfer protects nonhuman primates from mucosal simian-human immunodeficiency virus Infection. J Virol 2015; 89(16): 8334-45.
[104]
Johnson PR, Schnepp BC, Zhang J, et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat Med 2009; 15(8): 901-6.
[105]
Abdel-Motal UM, Harbison C, Han T, et al. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. Gene Ther 2014; 21(9): 802-10.
[106]
Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med 2015; 7(319): 319ra206.
[107]
Mayer KH, Seaton K, Huang Y, et al. Clinical safety and pharmacokinetics of IV and SC VRC01, a broadly neutralizing mAb. Conference on Retroviruses and Opportunistic Infections (CROI). 2016 Feb. 22-25; Boston, MA.
[108]
Astronomo R, Lemos MP, Narpala S, McElrath MJ. Rectal and vaginal biopsies from men and women infused intravenously with VRC01 show protection in ex vivo HIV-1 challenge. HIV Research for Prevention Meeting. Chicago. 2016.
[110]
Morris GC, Wiggins RC, Woodhall SC, et al. MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide. PLoS One 2014; 9(12): e116153.
[111]
Ma JK, Drossard J, Lewis D, et al. Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants. Plant Biotechnol J 2015; 13(8): 1106-20.
[112]
Whaley KJ, Zeitlin L. Preventing transmission: Plant-derived microbicides and mucosal vaccines for reproductive health. Vaccine 2005; 23(15): 1819-22.
Article Metrics
70
4