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Current HIV Research

Editor-in-Chief

ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Mini-Review Article

Monoclonal CCR5 Antibody: A Promising Therapy for HIV

Author(s): Li Zhao and Yu Lai*

Volume 21, Issue 2, 2023

Published on: 28 March, 2023

Page: [91 - 98] Pages: 8

DOI: 10.2174/1570162X21666230316110830

Price: $65

Abstract

HIV is one of the world's most devastating viral infections and has claimed tens of millions of lives worldwide since it was first identified in the 1980s. There is no cure for HIV infection. However, with tremendous progress in HIV diagnosis, prevention, and treatment, HIV has become a manageable chronic health disease. CCR5 is an important coreceptor used by HIV to infect target cells, and genetic deficiency of the chemokine receptor CCR5 confers a significant degree of protection against HIV infection. In addition, since CCR5 deficiency does not appear to cause any adverse health effects, targeting this coreceptor is a promising strategy for the treatment and prevention of HIV. Monoclonal antibodies are frequently used as therapeutics for many diseases and therefore are being used as a potential therapy for HIV-1 infection. This review reports on CCR5 antibody research in detail and describes the role and advantages of CCR5 antibodies in HIV prevention or treatment, introduces several main CCR5 antibodies, and discusses the future strategy of antibody-conjugated nanoparticles including the potential challenges. CCR5 antibodies may be a novel therapy for treating HIV infection effectively and could overcome the limitations of the currently available options.

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Graphical Abstract

[1]
World health statistics 2022: monitoring health for the SDGs, sustainable development goals. Geneva: World Health Organization 2022. Licence: CC BY-NC-SA 3.0 IGO.
[2]
Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 2004; 170(2): 229-38.
[PMID: 14734438]
[3]
Karuppusamy KV, Demosthenes JP, Venkatesan V, et al. The CCR5 gene edited CD34(+)CD90(+) hematopoietic stem cell population serves as an optimal graft source for HIV gene therapy. Front Immunol 2022; 13: 792684.
[4]
Kagan RM, Dunn KJ, Snell GP, Nettles RE, Kaufman HW. Trends in HIV-1 Drug resistance mutations from a U.S. Reference Laboratory from 2006 to 2017. AIDS Res Hum Retroviruses 2019; 35(8): 698-709.
[http://dx.doi.org/10.1089/aid.2019.0063] [PMID: 31169022]
[5]
Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 2005; 19(10): 1081-9.
[http://dx.doi.org/10.1097/01.aids.0000174455.01369.ad] [PMID: 15958840]
[6]
Hogg RS, Bangsberg DR, Lima VD, et al. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med 2006; 3(9): e356.
[http://dx.doi.org/10.1371/journal.pmed.0030356] [PMID: 16984218]
[7]
Grover D, Copas A, Green H, et al. What is the risk of mortality following diagnosis of multidrug-resistant HIV-1? J Antimicrob Chemother 2008; 61(3): 705-13.
[http://dx.doi.org/10.1093/jac/dkm522] [PMID: 18222956]
[8]
Rana AI, Castillo-Mancilla JR, Tashima KT, Landovitz RL. Advances in long-acting agents for the treatment of HIV infection. Drugs 2020; 80(6): 535-45.
[http://dx.doi.org/10.1007/s40265-020-01284-1] [PMID: 32180205]
[9]
Thompson MA. The return of PRO 140, a CCR5-directed mAb. Curr Opin HIV AIDS 2018; 13(4): 346-53.
[http://dx.doi.org/10.1097/COH.0000000000000479] [PMID: 29708899]
[10]
Moore JP, Trkola A, Dragic T. Co-receptors for HIV-1 entry. Curr Opin Immunol 1997; 9(4): 551-62.
[http://dx.doi.org/10.1016/S0952-7915(97)80110-0] [PMID: 9287172]
[11]
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393(6686): 648-59.
[http://dx.doi.org/10.1038/31405] [PMID: 9641677]
[12]
Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360(7): 692-8.
[http://dx.doi.org/10.1056/NEJMoa0802905] [PMID: 19213682]
[13]
Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 2019; 568(7751): 244-8.
[http://dx.doi.org/10.1038/s41586-019-1027-4] [PMID: 30836379]
[14]
Mohamed H, Gurrola T, Berman R, et al. Targeting CCR5 as a component of an HIV-1 therapeutic strategy. Front Immunol 2022; 12: 816515.
[http://dx.doi.org/10.3389/fimmu.2021.816515] [PMID: 35126374]
[15]
Olson WC, Jacobson JM. CCR5 monoclonal antibodies for HIV-1 therapy. Curr Opin HIV AIDS 2009; 4(2): 104-11.
[http://dx.doi.org/10.1097/COH.0b013e3283224015] [PMID: 19339948]
[16]
Lee B, Sharron M, Blanpain C, et al. Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem 1999; 274(14): 9617-26.
[http://dx.doi.org/10.1074/jbc.274.14.9617] [PMID: 10092648]
[17]
Venuti A, Pastori C, Lopalco L. The role of natural antibodies to CC chemokine receptor 5 in HIV infection. Front Immunol 2017; 8: 1358.
[http://dx.doi.org/10.3389/fimmu.2017.01358] [PMID: 29163468]
[18]
Pastori C, Weiser B, Barassi C, et al. Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression. Blood 2006; 107(12): 4825-33.
[http://dx.doi.org/10.1182/blood-2005-06-2463] [PMID: 16522810]
[19]
Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis 2010; 201(10): 1481-7.
[http://dx.doi.org/10.1086/652190] [PMID: 20377413]
[20]
Cavacini LA, Samore MH, Gambertoglio J, et al. Phase I study of a human monoclonal antibody directed against the CD4-binding site of HIV type 1 glycoprotein 120. AIDS Res Hum Retroviruses 1998; 14(7): 545-50.
[http://dx.doi.org/10.1089/aid.1998.14.545] [PMID: 9591708]
[21]
Lalezari J, Yadavalli GK, Para M, et al. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 2008; 197(5): 721-7.
[http://dx.doi.org/10.1086/527327] [PMID: 18266604]
[22]
Olson WC, Rabut GEE, Nagashima KA, et al. Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5. J Virol 1999; 73(5): 4145-55.
[http://dx.doi.org/10.1128/JVI.73.5.4145-4155.1999] [PMID: 10196311]
[23]
Biswas P, Tambussi G, Lazzarin A. Access denied? The status of co-receptor inhibition to counter HIV entry. Expert Opin Pharmacother 2007; 8(7): 923-33.
[http://dx.doi.org/10.1517/14656566.8.7.923] [PMID: 17472538]
[24]
Li L, Sun T, Yang K, Zhang P, Jia WQ. Monoclonal CCR5 antibody for treatment of people with HIV infection. Cochrane Database Syst Rev 2010; (12): CD008439.
[PMID: 21154397]
[25]
Wood A, Armour D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog Med Chem 2005; 43: 239-71.
[26]
Biswas P, Nozza S, Scarlatti G, Lazzarin A, Tambussi G. Oral CCR5 inhibitors: Will they make it through? Expert Opin Investig Drugs 2006; 15(5): 451-64.
[http://dx.doi.org/10.1517/13543784.15.5.451] [PMID: 16634684]
[27]
Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 2007; 81(5): 2359-71.
[http://dx.doi.org/10.1128/JVI.02006-06] [PMID: 17182681]
[28]
Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 2008; 198(9): 1345-52.
[http://dx.doi.org/10.1086/592169] [PMID: 18771406]
[29]
Dhody K, Pourhassan N, Kazempour K, et al. PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection. HIV Clin Trials 2018; 19(3): 85-93.
[http://dx.doi.org/10.1080/15284336.2018.1452842] [PMID: 29676212]
[30]
Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2006; 50(10): 3289-96.
[http://dx.doi.org/10.1128/AAC.00699-06] [PMID: 17005807]
[31]
Progenics, Inc. Progenics Pharmaceuticals’ HIV Drug, PRO 140, Receives FDA Fast-Track Designation. 2006. Available from : http://files.shareho-lder.com/downloads/PGNX/0x0x35170/272396d4-aea5-4daf-9ab3-9101e4c41368/192542.pdf
[32]
Hutchings CJ. A review of antibody-based therapeutics targeting G protein-coupled receptors: An update. Expert Opin Biol Ther 2020; 20(8): 925-35.
[http://dx.doi.org/10.1080/14712598.2020.1745770] [PMID: 32264722]
[33]
Chang XL, Webb GM, Wu HL, et al. Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission. Nat Commun 2021; 12(1): 3343.
[http://dx.doi.org/10.1038/s41467-021-23697-6] [PMID: 34099693]
[34]
Chang XL, Reed JS, Webb GM, et al. Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species. PLoS Pathog 2022; 18(3): e1010396.
[http://dx.doi.org/10.1371/journal.ppat.1010396] [PMID: 35358290]
[35]
Haberer JE. Current concepts for PrEP adherence in the PrEP revolution. Curr Opin HIV AIDS 2016; 11(1): 10-7.
[http://dx.doi.org/10.1097/COH.0000000000000220] [PMID: 26633638]
[36]
Markowitz M, Grossman H, Anderson PL, et al. Newly acquired infection with multidrug-resistant HIV-1 in a patient adherent to preexposure prophylaxis. J Acquir Immune Defic Syndr 2017; 76(4): e104-6.
[http://dx.doi.org/10.1097/QAI.0000000000001534] [PMID: 29076941]
[37]
Radzio-Basu J, Council O. Cong M, et al. Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection. Nat Commun 2019; 10(1): 2005.
[http://dx.doi.org/10.1038/s41467-019-10047-w] [PMID: 31043606]
[38]
Qi B, Fang Q, Liu S, et al. Advances of CCR5 antagonists: From small molecules to macromolecules. Eur J Med Chem 2020; 208: 112819.
[http://dx.doi.org/10.1016/j.ejmech.2020.112819] [PMID: 32947226]
[39]
Burger DR, Parker Y, Guinta K, Lindner D. PRO 140 monoclonal antibody to CCR5 prevents acute xenogeneic graft-versus-host disease in NOD-scid IL-2Rynull mice. Biol Blood Marrow Transplant 2018; 24(2): 260-6.
[http://dx.doi.org/10.1016/j.bbmt.2017.10.041] [PMID: 29128556]
[40]
Jiao X, Wang M, Zhang Z, et al. Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy. Breast Cancer Res 2021; 23(1): 11.
[http://dx.doi.org/10.1186/s13058-021-01391-1] [PMID: 33485378]
[41]
Skendelas JP, Phan D, Caputo V, et al. Novel CCR5 antagonist for the treatment of mild-moderate COVID-19 infection after lung transplant. J Heart Lung Transplant 2021; 40(4): S315.
[http://dx.doi.org/10.1016/j.healun.2021.01.891]
[42]
Lalezari J, Lederman M, Yadavalli G, et al. A Phase I, dose-escalation, placebo-controlled study of a fully human monoclonal antibody (CCR5mAb004) against CCR5 in patients with CCR5-tropic HIV-1 infection. Proceedings of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA. 2006; pp. 27-30.
[43]
Alyanakian MA, Bernatowska E, Scherrmann JM, Aucouturier P, Poplavsky JL. Pharmacokinetics of total immunoglobulin G and immunoglobulin G subclasses in patients undergoing replacement therapy for primary immunodeficiency syndromes. Vox Sang 2003; 84(3): 188-92.
[http://dx.doi.org/10.1046/j.1423-0410.2003.00278.x] [PMID: 12670367]
[44]
Björkander J, Nikoskelainen J, Leibl H, et al. Prospective open-label study of pharmacokinetics, efficacy and safety of a new 10% liquid intravenous immunoglobulin in patients with hypo- or agammaglobulinemia. Vox Sang 2006; 90(4): 286-93.
[http://dx.doi.org/10.1111/j.1423-0410.2006.00764.x] [PMID: 16635071]
[45]
Veazey RS, Ketas TJ, Dufour J, et al. Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis 2010; 202(5): 739-44.
[http://dx.doi.org/10.1086/655661] [PMID: 20629537]
[46]
Giguel F, Beebe L, Migone TS, Kuritzkes D. The anti-CCR5 mAb004 inhibits HIV-1 replication synergistically in combination with other antiretroviral agents but does not select for resistance during in vitro passage. 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA. 2006.
[47]
Latinovic O, Le N, Reitz M, et al. Synergistic inhibition of R5 HIV-1 by maraviroc and CCR5 antibody HGS004 in primary cells: implications for treatment and prevention. AIDS 2011; 25(9): 1232-5.
[http://dx.doi.org/10.1097/QAD.0b013e3283471edb] [PMID: 21505306]
[48]
Latinovic O, Reitz M, Le NM, et al. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells. Virology 2011; 411(1): 32-40.
[http://dx.doi.org/10.1016/j.virol.2010.12.029] [PMID: 21232779]
[49]
Chain B, Arnold J, Akthar S, et al. A linear epitope in the N-Terminal domain of CCR5 and its interaction with antibody. PLoS One 2015; 10(6): e0128381.
[http://dx.doi.org/10.1371/journal.pone.0128381] [PMID: 26030924]
[50]
Ji C, Brandt M, Dioszegi M, et al. Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities. Antiviral Res 2007; 74(2): 125-37.
[http://dx.doi.org/10.1016/j.antiviral.2006.11.003] [PMID: 17166600]
[51]
Ji C, Zhang J, Dioszegi M, et al. CCR5 small-molecule antagonists and monoclonal antibodies exert potent synergistic antiviral effects by cobinding to the receptor. Mol Pharmacol 2007; 72(1): 18-28.
[http://dx.doi.org/10.1124/mol.107.035055] [PMID: 17392523]
[52]
Zhang J, Rao E, Dioszegi M, et al. The second extracellular loop of CCR5 contains the dominant epitopes for highly potent anti-human immunodeficiency virus monoclonal antibodies. Antimicrob Agents Chemother 2007; 51(4): 1386-97.
[http://dx.doi.org/10.1128/AAC.01302-06] [PMID: 17242138]
[53]
Jekle A, Chhabra M, Lochner A, et al. Epitope switching as a novel escape mechanism of HIV to CCR5 monoclonal antibodies. Antimicrob Agents Chemother 2010; 54(2): 734-41.
[http://dx.doi.org/10.1128/AAC.00841-09] [PMID: 19995923]
[54]
Pfeifer N, Walter H, Lengauer T. Association between HIV-1 coreceptor usage and resistance to broadly neutralizing antibodies. J Acquir Immune Defic Syndr 2014; 67(2): 107-12.
[http://dx.doi.org/10.1097/QAI.0000000000000283] [PMID: 25072615]
[55]
Lewis GK, Pazgier M, Evans DT, et al. Beyond viral neutralization. AIDS Res Hum Retroviruses 2017; 33(8): 760-4.
[http://dx.doi.org/10.1089/aid.2016.0299] [PMID: 28084796]
[56]
Prathipati PK, Mandal S, Destache CJ. A review of CCR5 antibodies against HIV: Current and future aspects. Ther Deliv 2019; 10(2): 107-12.
[http://dx.doi.org/10.4155/tde-2018-0072] [PMID: 30729884]
[57]
Margolis DA, Brinson CC, Smith GHR, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis 2015; 15(10): 1145-55.
[http://dx.doi.org/10.1016/S1473-3099(15)00152-8] [PMID: 26201299]
[58]
Destache CJ, Belgum T, Christensen K, Shibata A, Sharma A, Dash A. Combination antiretroviral drugs in PLGA nanoparticle for HIV-1. BMC Infect Dis 2009; 9(1): 198.
[http://dx.doi.org/10.1186/1471-2334-9-198] [PMID: 20003214]
[59]
Mandal S, Belshan M, Holec A, Zhou Y, Destache CJ. An enhanced emtricitabine-loaded long-acting nanoformulation for prevention or treatment of HIV infection. Antimicrob Agents Chemother 2016; 61(1): 61.
[PMID: 27821449]
[60]
Duan J, Freeling JP, Koehn J, Shu C, Ho RJY. Evaluation of atazanavir and darunavir interactions with lipids for developing pH-responsive anti-HIV drug combination nanoparticles. J Pharm Sci 2014; 103(8): 2520-9.
[http://dx.doi.org/10.1002/jps.24046] [PMID: 24948204]
[61]
Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet 2017; 390(10101): 1499-510.
[http://dx.doi.org/10.1016/S0140-6736(17)31917-7] [PMID: 28750935]
[62]
Prathipati PK, Mandal S, Pon G, Vivekanandan R, Destache CJ. Pharmacokinetic and tissue distribution profile of long acting tenofovir alafenamide and elvitegravir loaded nanoparticles in humanized mice model. Pharm Res 2017; 34(12): 2749-55.
[http://dx.doi.org/10.1007/s11095-017-2255-7] [PMID: 28905173]
[63]
Rusconi S, Marcotullio S, Cingolani A. Long-acting agents for HIV infection: Biological aspects, role in treatment and prevention, and patient’s perspective. New Microbiol 2017; 40(2): 75-9.
[PMID: 28368071]
[64]
Tang X, Liang Y, Liu X, et al. PLGA-PEG nanoparticles coated with anti-CD45RO and loaded with HDAC plus protease inhibitors activate latent HIV and inhibit viral spread. Nanoscale Res Lett 2015; 10(1): 413.
[http://dx.doi.org/10.1186/s11671-015-1112-z] [PMID: 26489856]
[65]
Glass JJ, Yuen D, Rae J, et al. Human immune cell targeting of protein nanoparticles – caveospheres. Nanoscale 2016; 8(15): 8255-65.
[http://dx.doi.org/10.1039/C6NR00506C] [PMID: 27031090]
[66]
Zalevsky J, Chamberlain AK, Horton HM, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 2010; 28(2): 157-9.
[http://dx.doi.org/10.1038/nbt.1601] [PMID: 20081867]

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