Abstract
Prior to the nineteenth century, infectious disease was one of the leading causes of death. Human life expectancy has roughly doubled over the past century as a result of the development of antibiotics and vaccines. However, the emergence of antibiotic-resistant superbugs brings new challenges. The side effects of broad-spectrum antibiotics, such as causing antimicrobial resistance and destroying the normal flora, often limit their applications. Furthermore, the development of new antibiotics has lagged far behind the emergence and spread of antibiotic resistance. On the other hand, the genome complexity of bacteria makes it difficult to create effective vaccines. Therefore, novel therapeutic agents in supplement to antibiotics and vaccines are urgently needed to improve the treatment of infections. In recent years, monoclonal antibodies (mAbs) have achieved remarkable clinical success in a variety of fields. In the treatment of infectious diseases, mAbs can play functions through multiple mechanisms, including toxins neutralization, virulence factors inhibition, complement-mediated killing activity, and opsonic phagocytosis. Toxins and bacterial surface components are good targets to generate antibodies against. The U.S. FDA has approved three monoclonal antibody drugs, and there are numerous candidates in the preclinical or clinical trial stages. This article reviews recent advances in the research and development of anti-bacterial monoclonal antibody drugs in order to provide a valuable reference for future studies in this area.
Key points
• Novel drugs against antibiotic-resistant superbugs are urgently required
• Monoclonal antibodies can treat bacterial infections through multiple mechanisms
• There are many anti-bacterial monoclonal antibodies developed in recent years and some candidates have entered the preclinical or clinical stages of development
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adamo R, Margarit I (2018) Fighting antibiotic-resistant Klebsiella pneumoniae with "sweet" immune targets. mBio 9(3):e00874–18. https://doi.org/10.1128/mBio.00874-18
Aguilar JL, Varshney AK, Pechuan X, Dutta K, Nosanchuk JD, Fries BC (2017) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence 8(6):741–750. https://doi.org/10.1080/21505594.2016.1231295
Al-Sharqi A, Apun K, Vincent M, Kanakaraju D, Bilung LM, Sum MSH (2020) Investigation of the antibacterial activity of Ag-NPs conjugated with a specific antibody against Staphylococcus aureus after photoactivation. J Appl Microbiol 128(1):102–115. https://doi.org/10.1111/jam.14471
Altai M, Liu H, Orlova A, Tolmachev V, Graslund T (2016) Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin. Int J Oncol 49(3):1185–1194. https://doi.org/10.3892/ijo.2016.3614
Badarau A, Rouha H, Malafa S, Battles MB, Walker L, Nielson N, Dolezilkova I, Teubenbacher A, Banerjee S, Maierhofer B, Weber S, Stulik L, Logan DT, Welin M, Mirkina I, Pleban C, Zauner G, Gross K, Jagerhofer M, Magyarics Z, Nagy E (2016) Context matters: the importance of dimerization-induced conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of neutralizing antibodies. MAbs 8(7):1347–1360. https://doi.org/10.1080/19420862.2016.1215791
Di Bella S, Ascenzi P, Siarakas S, Petrosillo N, di Masi A (2016) Clostridium difficile Toxins A and B: insights into pathogenic properties and extraintestinal effects. Toxins (Basel) 8(5):134. https://doi.org/10.3390/toxins8050134
Berry JD, Gaudet RG (2011) Antibodies in infectious diseases: polyclonals, monoclonals and niche biotechnology. New Biotechnol 28(5):489–501. https://doi.org/10.1016/j.nbt.2011.03.018
Biron B, Beck K, Dyer D, Mattix M, Twenhafel N, Nalca A (2015) Efficacy of ETI-204 monoclonal antibody as an adjunct therapy in a New Zealand white rabbit partial survival model for inhalational anthrax. Antimicrob Agents Chemother 59(4):2206–2214. https://doi.org/10.1128/AAC.04593-14
Bugg TD, Rodolis MT, Mihalyi A, Jamshidi S (2016) Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage varphiX174 lysis protein E, and cationic antibacterial peptides. Bioorg Med Chem 24(24):6340–6347. https://doi.org/10.1016/j.bmc.2016.03.018
Cao J, Yi F, Tian Q, Dang G, Si W, Liu S, Yu S (2017) Targeting the gram-negative bacteria peptidoglycan synthase MraY as a new approach for monoclonal antibody anti-bacterial activity. Hum Vaccines Immunotherapeutics 13(9):2086–2091. https://doi.org/10.1080/21645515.2017.1337613
Cerca N, Jefferson KK, Maira-Litran T, Pier DB, Kelly-Quintos C, Goldmann DA, Azeredo J, Pier GB (2007) Molecular basis for preferential protective efficacy of antibodies directed to the poorly acetylated form of staphylococcal poly-N-acetyl-beta-(1–6)-glucosamine. Infect Immun 75(7):3406–3413. https://doi.org/10.1128/IAI.00078-07
Chahine EB, Cho JC, Worley MV (2018) Bezlotoxumab for the prevention of Clostridium difficile recurrence. Consult Pharm 33(2):89–97. https://doi.org/10.4140/TCP.n.2018.89
Chaturvedi D, Mahalakshmi R (2017) Transmembrane beta-barrels: evolution, folding and energetics. Biochim Biophys Acta 1859(12):2467–2482. https://doi.org/10.1016/j.bbamem.2017.09.020
Chen X, Shi M, Tong X, Kim HK, Wang LX, Schneewind O, Missiakas D (2020) Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies. Proc Natl Acad Sci U S A 117(37):22992–23000. https://doi.org/10.1073/pnas.2003621117
Chen X, Schneewind O, Missiakas D (2022) Engineered human antibodies for the opsonization and killing of Staphylococcus aureus. Proc Natl Acad Sci U S A 119(4):e2114478119. https://doi.org/10.1073/pnas.2114478119
Cohen TS, Hilliard JJ, Jones-Nelson O, Keller AE, O’Day T, Tkaczyk C, DiGiandomenico A, Hamilton M, Pelletier M, Wang Q, Diep BA, Le VT, Cheng L, Suzich J, Stover CK, Sellman BR (2016) Staphylococcus aureus α toxin potentiates opportunistic bacterial lung infections. Sci Transl Med 8(329):329ra31. https://doi.org/10.1126/scitranslmed.aad9922
de Vor L, van Dijk B, van Kessel K, Kavanaugh JS, de Haas C, Aerts PC, Viveen MC, Boel EC, Fluit AC, Kwiecinski JM, Krijger GC, Ramakers RM, Beekman FJ, Dadachova E, Lam MG, Vogely HC, van der Wal BC, van Strijp JA, Horswill AR, Weinans H, Rooijakkers SH (2022) Human monoclonal antibodies against Staphylococcus aureus surface antigens recognize in vitro and in vivo biofilm. Elife 11:e67301. https://doi.org/10.7554/eLife.67301
Deng R, Zhou C, Li D, Cai H, Sukumaran S, Carrasco-Triguero M, Saad O, Nazzal D, Lowe C, Ramanujan S, Kamath AV (2019) Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against Staphylococcus aureus. MAbs 11(6):1162–1174. https://doi.org/10.1080/19420862.2019.1627152
Diago-Navarro E, Calatayud-Baselga I, Sun D, Khairallah C, Mann I, Ulacia-Hernando A, Sheridan B, Shi M, Fries BC (2017) Antibody-based immunotherapy to treat and prevent infection with hypervirulent Klebsiella pneumoniae. Clin Vaccine Immunol 24(1):e00456–16. https://doi.org/10.1128/cvi.00456-16
Diago-Navarro E, Motley MP, Ruiz-Peréz G, Yu W, Austin J, Seco BMS, Xiao G, Chikhalya A, Seeberger PH, Fries BC (2018) Novel, broadly reactive anticapsular antibodies against carbapenem-resistant Klebsiella pneumoniae protect from infection. mBio 9(2):e00091–18. https://doi.org/10.1128/mBio.00091-18
DiGiandomenico A, Keller AE, Gao C, Rainey GJ, Warrener P, Camara MM, Bonnell J, Fleming R, Bezabeh B, Dimasi N, Sellman BR, Hilliard J, Guenther CM, Datta V, Zhao W, Gao C, Yu XQ, Suzich JA, Stover CK (2014) A multifunctional bispecific antibody protects against Pseudomonas aeruginosa. Sci Transl Med 6(262):262ra155. https://doi.org/10.1126/scitranslmed.3009655
Doyle MT, Bernstein HD (2019) Bacterial outer membrane proteins assemble via asymmetric interactions with the BamA beta-barrel. Nat Commun 10(1):3358. https://doi.org/10.1038/s41467-019-11230-9
François B, Jafri HS, Chastre J, Sánchez-García M, Eggimann P, Dequin PF, Huberlant V, Viña Soria L, Boulain T, Bretonnière C, Pugin J, Trenado J, Hernandez Padilla AC, Ali O, Shoemaker K, Ren P, Coenjaerts FE, Ruzin A, Barraud O, Timbermont L, Lammens C, Pierre V, Wu Y, Vignaud J, Colbert S, Bellamy T, Esser MT, Dubovsky F, Bonten MJ, Goossens H, Laterre PF (2021) Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. Lancet Infect Dis 21(9):1313–1323. https://doi.org/10.1016/s1473-3099(20)30995-6
Francois B, Sanchez MG, Eggimann P, Dequin P, Laterre P, Huberlant V, Escudero D, Boulain T, Bretonniere C, Pugin J, Alvarez JT, Ali O, Shoemaker K, Ruzin A, Vandamme D, Colbert S, Bellamy T, Dubovsky F, Jafri H, Grp SS (2019) Suvratoxumab reduces Staphylococcus aureus pneumonia in high-risk ICU patients: results of the SAATELLITE study. Am J Respir Crit Care Med 199:A7358. https://doi.org/10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A7358
Gao F, Zhai G, Wang H, Lu L, Xu J, Zhu J, Chen D, Lu H (2020) Protective effects of anti-alginate monoclonal antibody against Pseudomonas aeruginosa infection of HeLa cells. Microb Pathog 145:104240. https://doi.org/10.1016/j.micpath.2020.104240
Henning LN, Carpenter S, Stark GV, Serbina NV (2018) Development of protective immunity in New Zealand white rabbits challenged with Bacillus anthracis spores and treated with antibiotics and obiltoxaximab, a monoclonal antibody against protective antigen. Antimicrob Agents Chemother 62(2):e01590-e1617. https://doi.org/10.1128/AAC.01590-17
Hnasko R, Lin AV, McGarvey JA (2019) Rapid detection of Staphylococcal Enterotoxin-B by lateral flow assay. Monoclon Antib Immunodiagn Immunother 38(5):209–212. https://doi.org/10.1089/mab.2019.0028
Hoelzgen F, Zalk R, Alcalay R, Cohen-Schwartz S, Garau G, Shahar A, Mazor O, Frank GA (2021) Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop. Acta Crystallographica Section d, Structural Biology 77(Pt 9):1197–1205. https://doi.org/10.1107/s2059798321007816
Horna G, Ruiz J (2021) Type 3 secretion system of Pseudomonas aeruginosa. Microbiol Res 246:126719. https://doi.org/10.1016/j.micres.2021.126719
Hua L, Hilliard JJ, Shi Y, Tkaczyk C, Cheng LI, Yu X, Datta V, Ren S, Feng H, Zinsou R, Keller A, O’Day T, Du Q, Cheng L, Damschroder M, Robbie G, Suzich J, Stover CK, Sellman BR (2014) Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia. Antimicrob Agents Chemother 58(2):1108–1117. https://doi.org/10.1128/aac.02190-13
Hua L, Cohen TS, Shi Y, Datta V, Hilliard JJ, Tkaczyk C, Suzich J, Stover CK, Sellman BR (2015) MEDI4893* Promotes survival and extends the antibiotic treatment window in a Staphylococcus aureus immunocompromised pneumonia model. Antimicrob Agents Chemother 59(8):4526–4532. https://doi.org/10.1128/AAC.00510-15
Huang B, Xie T, Rotstein D, Fang H, Frucht DM (2015) Passive immunotherapy protects against enteric invasion and lethal sepsis in a murine model of gastrointestinal anthrax. Toxins (basel) 7(10):3960–3976. https://doi.org/10.3390/toxins7103960
Ivanova K, Ivanova A, Ramon E, Hoyo J, Sanchez-Gomez S, Tzanov T (2020) Antibody-enabled antimicrobial nanocapsules for selective elimination of Staphylococcus aureus. ACS Appl Mater Interfaces 12(32):35918–35927. https://doi.org/10.1021/acsami.0c09364
Jain R, Beckett VV, Konstan MW, Accurso FJ, Burns JL, Mayer-Hamblett N, Milla C, VanDevanter DR, Chmiel JF, Group KAS (2018) KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa. J Cyst Fibros: Off J Eur Cys Fibros Soc 17(4):484–491. https://doi.org/10.1016/j.jcf.2017.12.006
Kajihara KK, Pantua H, Hernandez-Barry H, Hazen M, Deshmukh K, Chiang N, Ohri R, Castellanos ER, Martin L, Matsumoto ML, Payandeh J, Storek KM, Schneider K, Smith PA, Koehler MFT, Tsai SP, Vandlen R, Loyet KM, Nakamura G, Pillow T, Seshasayee D, Kapadia SB, Hazenbos WLW (2021) Potent killing of Pseudomonas aeruginosa by an antibody-antibiotic conjugate. mBio 12(3):e0020221. https://doi.org/10.1128/mBio.00202-21
Kane TL, Carothers KE, Lee SW (2018) Virulence factor targeting of the bacterial pathogen Staphylococcus aureus for vaccine and therapeutics. Curr Drug Targets 19(2):111–127. https://doi.org/10.2174/1389450117666161128123536
Karau MJ, Tilahun ME, Krogman A, Osborne BA, Goldsby RA, David CS, Mandrekar JN, Patel R, Rajagopalan G (2017) Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producing Staphylococcus aureus. Virulence 8(7):1148–1159. https://doi.org/10.1080/21505594.2016.1267894
Kaufmann SH (2017) Remembering Emil von Behring: from tetanus treatment to antibody cooperation with phagocytes. mBio 8(1):e00117–17. https://doi.org/10.1128/mBio.00117-17
Kelly-Quintos C, Cavacini LA, Posner MR, Goldmann D, Pier GB (2006) Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetylglucosamine. Infect Immun 74(5):2742–2750. https://doi.org/10.1128/IAI.74.5.2742-2750.2006
Kim HK, Emolo C, DeDent AC, Falugi F, Missiakas DM, Schneewind O (2012) Protein A-specific monoclonal antibodies and prevention of Staphylococcus aureus disease in mice. Infect Immun 80(10):3460–3470. https://doi.org/10.1128/IAI.00230-12
Kobayashi SD, Porter AR, Freedman B, Pandey R, Chen L, Kreiswirth BN, Deleo FR (2018) Antibody-mediated killing of carbapenem-resistant ST258 Klebsiella pneumoniae by human neutrophils. Mbio 9(2):e00297–18. https://doi.org/10.1128/mBio.00297-18
Kufel WD, Devanathan AS, Marx AH, Weber DJ, Daniels LM (2017) Bezlotoxumab: a novel agent for the prevention of recurrent Clostridium difficile infection. Pharmacotherapy 37(10):1298–1308. https://doi.org/10.1002/phar.1990
LaRocca TJ, Katona LI, Thanassi DG, Benach JL (2008) Bactericidal action of a complement-independent antibody against relapsing fever Borrelia resides in its variable region. J Immunol 180(9):6222–6228. https://doi.org/10.4049/jimmunol.180.9.6222
LaRocca TJ, Holthausen DJ, Hsieh C, Renken C, Mannella CA, Benach JL (2009) The bactericidal effect of a complement-independent antibody is osmolytic and specific to Borrelia. Proc Natl Acad Sci U S A 106(26):10752–10757. https://doi.org/10.1073/pnas.0901858106
Le H, Arnoult C, Dé E, Schapman D, Galas L, Le Cerf D, Karakasyan C (2021) Antibody-conjugated nanocarriers for targeted antibiotic delivery: application in the treatment of bacterial biofilms. Biomacromol 22(4):1639–1653. https://doi.org/10.1021/acs.biomac.1c00082
Le HN, Quetz JS, Tran VG, Le VTM, Aguiar-Alves F, Pinheiro MG, Cheng L, Yu L, Sellman BR, Stover CK, DiGiandomenico A, Diep BA (2018) MEDI3902 correlates of protection against severe Pseudomonas aeruginosa pneumonia in a rabbit acute pneumonia model. Antimicrob Agents Chemother 62(5):e02565–17. https://doi.org/10.1128/aac.02565-17
Lehar SM, Pillow T, Xu M, Staben L, Kajihara KK, Andlen RV, DePalatis L, Raab H, Hazenbos WL, Morisaki JH, Kim J, Park S, Darwish M, Lee B-C, Hernandez H, Loyet KM, Lupardus P, Fong R, Yan D, Halouni CC, Luis E, Khalfin Y, Plise E, Heong JC, Lyssikatos JP, Strandh M, Koefoed K, Andersen PS, Flygare JA, Tan MW, Brown EJ, Ariathasan SM (2015) Novel antibody-antibiotic conjugate eliminates intracellular S aureus. Nature 527(7578):323-+. https://doi.org/10.1038/nature16057
Leysath CE, Monzingo AF, Maynard JA, Barnett J, Georgiou G, Iverson BL, Robertus JD (2009) Crystal structure of the engineered neutralizing antibody M18 complexed to domain 4 of the anthrax protective antigen. J Mol Biol 387(3):680–693. https://doi.org/10.1016/j.jmb.2009.02.003
Liu S, Schubert RL, Bugge TH, Leppla SH (2003) Anthrax toxin: structures, functions and tumour targeting. Expert Opin Biol Ther 3(5):843–853. https://doi.org/10.1517/14712598.3.5.843
Luciani M, Lannetti L (2017) Monoclonal antibodies and bacterial virulence. Virulence 8(6):635–636. https://doi.org/10.1080/21505594.2017.1292199
Mariathasan S, Tan MW (2017) Antibody-antibiotic conjugates: a novel therapeutic platform against bacterial infections. Trends Mol Med 23(2):135–149. https://doi.org/10.1016/j.molmed.2016.12.008
Mazumdar S (2009) Raxibacumab. Mabs 1(6):531–538. https://doi.org/10.4161/mabs.1.6.10195
McConnell MJ (2019) Where are we with monoclonal antibodies for multidrug-resistant infections? Drug Discov Today 24(5):1132–1138. https://doi.org/10.1016/j.drudis.2019.03.002
Migone T-S, Subramanian GM, Zhong J, Healey LM, Corey A, Devalaraja M, Lo L, Ullrich S, Zimmerman J, Chen A, Lewis M, Meister G, Gillum K, Sanford D, Mott J, Bolmer SD (2009) Raxibacumab for the treatment of inhalational anthrax. N Engl J Med 361(2):135–144. https://doi.org/10.1056/NEJMoa0810603
Milla CE, Chmiel JF, Accurso FJ, VanDevanter DR, Konstan MW, Yarranton G, Geller DE, Group KBS (2014) Anti-PcrV antibody in cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection. Pediatr Pulmonol 49(7):650–8. https://doi.org/10.1002/ppul.22890
Mishra M, Byrd MS, Sergeant S, Azad AK, Parsek MR, McPhail L, Schlesinger LS, Wozniak DJ (2012) Pseudomonas aeruginosa Psl polysaccharide reduces neutrophil phagocytosis and the oxidative response by limiting complement-mediated opsonization. Cell Microbiol 14(1):95–106. https://doi.org/10.1111/j.1462-5822.2011.01704.x
Moayeri M, Leppla SH, Vrentas C, Pomerantsev AP, Liu S (2015) Anthrax pathogenesis. Annu Rev Microbiol 69:185–208. https://doi.org/10.1146/annurev-micro-091014-104523
Motley M, Kasturi B, C FB (2019) Monoclonal antibody-based therapies for bacterial infections. Curr Opin Infect Dis 32(3):210–216. https://doi.org/10.1097/QCO.0000000000000539
Motley MP, Diago-Navarro E, Banerjee K, Inzerillo S, Fries BC (2020) The role of IgG subclass in antibody-mediated protection against carbapenem-resistant Klebsiella pneumoniae. mBio 11(5):e02059–20. https://doi.org/10.1128/mBio.02059-20
Nagy CF, Leach TS, Hoffman JH, Czech A, Carpenter SE, Guttendorf R (2016) Pharmacokinetics and tolerability of obiltoxaximab: a report of 5 healthy volunteer studies. Clin Ther 38(9):2083-2097.e7. https://doi.org/10.1016/j.clinthera.2016.07.170
Nagy E, Nagy G, Power CA, Badarau A, Szijarto V (2017) Anti-bacterial monoclonal antibodies. Adv Exp Med Biol 1053:119–153. https://doi.org/10.1007/978-3-319-72077-7_7
Natali EN, Principato S, Ferlicca F, Bianchi F, Fontana LE, Faleri A, Pansegrau W, Surdo PL, Bartolini E, Santini L, Brunelli B, Giusti F, Veggi D, Ferlenghi I, Norais N, Scarselli M (2020) Synergic complement-mediated bactericidal activity of monoclonal antibodies with distinct specificity. FASEB J: Off Publ Fed Am Soc Exp Biol 34(8):10329–10341. https://doi.org/10.1096/fj.201902795R
Navalkele BD, Chopra T (2018) Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent Clostridium difficile infection. Biologics 12:11–21. https://doi.org/10.2147/BTT.S127099
Oganesyan V, Peng L, Damschroder MM, Cheng L, Sadowska A, Tkaczyk C, Sellman BR, Wu H, Dall’Acqua WF (2014) Mechanisms of neutralization of a human anti-alpha-toxin antibody. J Biol Chem 289(43):29874–29880. https://doi.org/10.1074/jbc.M114.601328
Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang X, Murgolo N, Ermakov G, DiNunzio E, Racine F, Karczewski J, Secore S, Ingram RN, Mayhood T, Strickland C, Therien AG (2014) Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem 289(26):18008–18021. https://doi.org/10.1074/jbc.M114.560748
Ortines RV, Liu H, Cheng LI, Cohen TS, Lawlor H, Gami A, Wang Y, Dillen CA, Archer NK, Miller RJ, Ashbaugh AG, Pinsker BL, Marchitto MC, Tkaczyk C, Stover CK, Sellman BR, Miller LS (2018) Neutralizing alpha-toxin accelerates healing of Staphylococcus aureus-infected wounds in nondiabetic and diabetic mice. Antimicrob Agents Chemother 62(3):e02288–17. https://doi.org/10.1128/AAC.02288-17
Patel M, Zipursky S, Orenstein W, Garon J, Zaffran M (2015) Polio endgame: the global introduction of inactivated polio vaccine. Expert Rev Vaccines 14(5):749–762. https://doi.org/10.1586/14760584.2015.1001750
Patel A, DiGiandomenico A, Keller AE, Smith TRF, Park DH, Ramos S, Schultheis K, Elliott STC, Mendoza J, Broderick KE, Wise MC, Yan J, Jiang J, Flingai S, Khan AS, Muthumani K, Humeau L, Cheng LI, Wachter-Rosati L, Stover CK, Sardesai NY, Weiner DB (2017) An engineered bispecific DNA-encoded IgG antibody protects against Pseudomonas aeruginosa in a pneumonia challenge model. Nat Commun 8(1):637. https://doi.org/10.1038/s41467-017-00576-7
Pennini ME, De Marco A, Pelletier M, Bonnell J, Cvitkovic R, Beltramello M, Cameroni E, Bianchi S, Zatta F, Zhao W, Xiao X, Camara MM, DiGiandomenico A, Semenova E, Lanzavecchia A, Warrener P, Suzich J, Wang Q, Corti D, Stover CK (2017) Immune stealth-driven O2 serotype prevalence and potential for therapeutic antibodies against multidrug resistant Klebsiella pneumoniae. Nat Commun 8(1):1991. https://doi.org/10.1038/s41467-017-02223-7
Pier GB, Boyer D, Preston M, Coleman FT, Llosa N, Mueschenborn-Koglin S, Theilacker C, Goldenberg H, Uchin J, Priebe GP, Grout M, Posner M, Cavacini L (2004) Human monoclonal antibodies to Pseudomonas aeruginosa alginate that protect against infection by both mucoid and nonmucoid strains. J Immunol (Baltimore, Md : 1950) 173(9):5671–8. https://doi.org/10.4049/jimmunol.173.9.5671
Pinkston KL, Singh KV, Gao P, Wilganowski N, Robinson H, Ghosh S, Azhdarinia A, Sevick-Muraca EM, Murray BE, Harvey BR (2014) Targeting pili in enterococcal pathogenesis. Infect Immun 82(4):1540–1547. https://doi.org/10.1128/IAI.01403-13
Powers ME, Kim HK, Wang Y, Wardenburg JB (2012) ADAM10 mediates vascular injury induced by Staphylococcus aureus alpha-hemolysin. J Infect Dis 206(3):352–356. https://doi.org/10.1093/infdis/jis192
Ram S, Lewis LA, Rice PA (2010) Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev 23(4):740–780. https://doi.org/10.1128/cmr.00048-09
Ray VA, Hill PJ, Stover CK, Roy S, Sen CK, Yu L, Wozniak DJ, DiGiandomenico A (2017) Anti-Psl targeting of Pseudomonas aeruginosa biofilms for neutrophil-mediated disruption. Sci Rep 7(1):16065. https://doi.org/10.1038/s41598-017-16215-6
Rello J, Parisella FR, Perez A (2019) Alternatives to antibiotics in an era of difficult-to-treat resistance: new insights. Expert Rev Clin Pharmacol 12(7):635–642. https://doi.org/10.1080/17512433.2019.1619454
Reyes-Robles T, Torres VJ (2017) Staphylococcus aureus pore-forming toxins. Curr Top Microbiol Immunol 409:121–144. https://doi.org/10.1007/82_2016_16
Rouha H, Badarau A, Visram ZC, Battles MB, Prinz B, Magyarics Z, Nagy G, Mirkina I, Stulik L, Zerbs M, Jaegerhofer M, Maierhofer B, Teubenbacher A, Dolezilkova I, Gross K, Banerjee S, Zauner G, Malafa S, Zmajkovic J, Maier S, Mabry R, Krauland E, Wittrup KD, Gerngross TU, Nagy E (2015) Five birds, one stone: neutralization of alpha-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibody. MAbs 7(1):243–254. https://doi.org/10.4161/19420862.2014.985132
Roux D, Pier GB, Skurnik D (2012) Magic bullets for the 21st century: the reemergence of immunotherapy for multi- and pan-resistant microbes. J Antimicrob Chemother 67(12):2785–2787. https://doi.org/10.1093/jac/dks335
Rukkawattanakul T, Sookrung N, Seesuay W, Onlamoon N, Diraphat P, Chaicumpa W, Indrawattana N (2017) Human scFvs that counteract bioactivities of Staphylococcus aureus TSST-1. Toxins (Basel) 9(2):50. https://doi.org/10.3390/toxins9020050
Sadarangani M (2018) Protection against invasive infections in children caused by encapsulated bacteria. Front Immunol 9:2674. https://doi.org/10.3389/fimmu.2018.02674
Saeed K, Esposito S, Gould I, Ascione T, Bassetti M, Bonnet E, Bouza E, Chan M, Davis JS, De Simone G, Dryden M, Gottlieb T, Hijazi K, Lye DC, Pagliano P, Petridou C, Righi E, Segreti J, Unal S, Yalcin AN (2018) Hot topics in necrotising skin and soft tissue infections. Int J Antimicrob Agents 52(1):1–10. https://doi.org/10.1016/j.ijantimicag.2018.02.012
Satlin MJ, Chen L, Patel G, Gomez-Simmonds A, Weston G, Kim AC, Seo SK, Rosenthal ME, Sperber SJ, Jenkins SG, Hamula CL, Uhlemann AC, Levi MH, Fries BC, Tang YW, Juretschko S, Rojtman AD, Hong T, Mathema B, Jacobs MR, Walsh TJ, Bonomo RA, Kreiswirth BN (2017) Multicenter clinical and molecular epidemiological analysis of bacteremia due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE epicenter of the United States. Antimicrob Agents Chemother 61(4):e02349-16. https://doi.org/10.1128/AAC.02349-16
Schiller ZA, Rudolph MJ, Toomey JR, Ejemel M, LaRochelle A, Davis SA, Lambert HS, Kern A, Tardo AC, Souders CA, Peterson E, Cannon RD, Ganesa C, Fazio F, Mantis NJ, Cavacini LA, Sullivan-Bolyai J, Hu LT, Embers ME, Klempner MS, Wang Y (2021) Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody. J Clin Invest 131(11):e144843. https://doi.org/10.1172/jci144843
Sewell EW, Brown ED (2014) Taking aim at wall teichoic acid synthesis: new biology and new leads for antibiotics. J Antibiot (tokyo) 67(1):43–51. https://doi.org/10.1038/ja.2013.100
Shokri R, Salouti M, Zanjani RS (2015) Anti protein A antibody-gold nanorods conjugate: a targeting agent for selective killing of methicillin resistant Staphylococcus aureus using photothermal therapy method. J Microbiol 53(2):116–121. https://doi.org/10.1007/s12275-015-4519-4
Skurnik D, Merighi M, Grout M, Gadjeva M, Maira-Litran T, Ericsson M, Goldmann DA, Huang SS, Datta R, Lee JC, Pier GB (2010) Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice. J Clin Invest 120(9):3220–3233. https://doi.org/10.1172/JCI42748
Skurnik D, Kropec A, Roux D, Theilacker C, Huebner J, Pier GB (2012) Natural antibodies in normal human serum inhibit Staphylococcus aureus capsular polysaccharide vaccine efficacy. Clin Infect Dis 55(9):1188–1197. https://doi.org/10.1093/cid/cis624
Solbach P, Dersch P, Bachmann O (2017) Individualized treatment strategies for Clostridium difficile infections. Internist (berl) 58(7):675–681. https://doi.org/10.1007/s00108-017-0268-2
Sorensen RU, Edgar D (2019) Specific antibody deficiencies in clinical practice. J Allergy Clin Immunol Pract 7(3):801–808. https://doi.org/10.1016/j.jaip.2019.01.024
Staben LR, Koenig SG, Lehar S, Vandlen R, Zhang D, Chuh J, Yu S-F, Ng C, Guo J, Liu Y, Fourie-O’Donohue A, Go M, Linghu X, Segraves NL, Wang T, Chen J, Wei B, Phillips GDL, Xu K, Kozak KR, Mariathasan S, Flygare JA, Pillow TH (2016) Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates. Nat Chem 8(12):1112–1119. https://doi.org/10.1038/nchem.2635
Storek KM, Vij R, Sun D, Smith PA, Koerber JT, Rutherford ST (2019) The Escherichia coli β-barrel assembly machinery is sensitized to perturbations under high membrane fluidity. J Bacteriol 201(1):e00517–18. https://doi.org/10.1128/jb.00517-18
Sundin C, Saleeb M, Spjut S, Qin L, Elofsson M (2021) Identification of small molecules blocking the Pseudomonas aeruginosa type III secretion system protein PcrV. Biomolecules 11(1):55. https://doi.org/10.3390/biom11010055
Szijártó V, Guachalla LM, Hartl K, Varga C, Badarau A, Mirkina I, Visram ZC, Stulik L, Power CA, Nagy E, Nagy G (2017) Endotoxin neutralization by an O-antigen specific monoclonal antibody: a potential novel therapeutic approach against Klebsiella pneumoniae ST258. Virulence 8(7):1203–1215. https://doi.org/10.1080/21505594.2017.1279778
Takahashi T, Joshi SG, Al-Saleem F, Ancharski D, Singh A, Nasser Z, Simpson LL (2009) Localization of the sites and characterization of the mechanisms by which anti-light chain antibodies neutralize the actions of the botulinum holotoxin. Vaccine 27(19):2616–2624. https://doi.org/10.1016/j.vaccine.2009.02.051
Thammavongsa V, Rauch S, Kim HK, Missiakas DM, Schneewind O (2015) Protein A-neutralizing monoclonal antibody protects neonatal mice against Staphylococcus aureus. Vaccine 33(4):523–526. https://doi.org/10.1016/j.vaccine.2014.11.051
Tim R, Valeria S, Jolanta L, M GL, Katarina S, Katharina H, Lukas S, Simone K, Felix L, Mohammed A-S, Jutta S-B, Moritz vF, Gereon G, Peter H, Sabrina K, Klaus H, Eszter N, Gabor N, Hedda W (2018) Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen. Nat Immunol 19(6):617–624. https://doi.org/10.1038/s41590-018-0106-2
Tkaczyk C, Semenova E, Sih YY, Rosenthal K, Oganesyan V, Warrener P, Stover CK, Sellman BR (2018) Alanine scanning mutagenesis of the MEDI4893 (Suvratoxumab) epitope reduces alpha toxin lytic activity in vitro and Staphylococcus aureus fitness in infection models. Antimicrobial Agents and Chemotherapy 62(11):e01033–18. https://doi.org/10.1128/aac.01033-18
Todoroki K, Yamada T, Mizuno H, Toyo’oka T (2018) Current mass spectrometric tools for the bioanalyses of therapeutic monoclonal antibodies and antibody-drug conjugates. Anal Sci 34(4):397–406. https://doi.org/10.2116/analsci.17R003
Underhill DM, Ozinsky A (2002) Phagocytosis of microbes: complexity in action. Annu Rev Immunol 20:825–852. https://doi.org/10.1146/annurev.immunol.20.103001.114744
Uppuluri P, Lin L, Alqarihi A, Luo G, Youssef EG, Alkhazraji S, Yount NY, Ibrahim BA, Bolaris MA, Edwards JE Jr, Swidergall M, Filler SG, Yeaman MR, Ibrahim AS (2018) The Hyr1 protein from the fungus Candida albicans is a cross kingdom immunotherapeutic target for Acinetobacter bacterial infection. PLoS Pathog 14(5):e1007056. https://doi.org/10.1371/journal.ppat.1007056
Varshney AK, Kuzmicheva GA, Lin J, Sunley KM, Bowling RA, Jr., Kwan T-Y, Mays HR, Rambhadran A, Zhang Y, Martin RL, Cavalier MC, Simard J, Shivaswamy S (2018) A natural human monoclonal antibody targeting Staphylococcus Protein A protects against Staphylococcus aureus bacteremia. Plos One 13(1):e0190537. https://doi.org/10.1371/journal.pone.0190537
Vij R, Lin ZH, Chiang N, Vernes JM, Storek KM, Park S, Chan J, Meng YG, Comps-Agrar L, Luan P, Lee S, Schneider K, Bevers J, Zilberleyb I, Tam C, Koth CM, Xu M, Gill A, Auerbach MR, Smith PA, Rutherford ST, Nakamura G, Seshasayee D, Payandeh J, Koerber JT (2018) A targeted boost-and-sort immunization strategy using Escherichia coli BamA identifies rare growth inhibitory antibodies. Sci Rep 8(1):7136. https://doi.org/10.1038/s41598-018-25609-z
Wagner EK, Maynard JA (2018) Engineering therapeutic antibodies to combat infectious diseases. Curr Opin Chem Eng 19:131–141. https://doi.org/10.1016/j.coche.2018.01.007
Wang Q, Chang CS, Pennini M, Pelletier M, Rajan S, Zha J, Chen Y, Cvitkovic R, Sadowska A, Heidbrink Thompson J, Yu Lin H, Barnes A, Rickert K, Wilson S, Stover CK, Dall’Acqua WF, Chowdhury PS, Xiao X (2016) Target-agnostic identification of functional monoclonal antibodies against Klebsiella pneumoniae multimeric MrkA fimbrial subunit. J Infect Dis 213(11):1800–1808. https://doi.org/10.1093/infdis/jiw021
Wang Y, Kern A, Boatright NK, Schiller ZA, Sadowski A, Ejemel M, Souders CA, Reimann KA, Hu L, Thomas WD Jr, Klempner MS (2016) Pre-exposure prophylaxis with OspA-specific human monoclonal antibodies protects mice against tick transmission of lyme disease spirochetes. J Infect Dis 214(2):205–211. https://doi.org/10.1093/infdis/jiw151
Wang Q, Chen Y, Cvitkovic R, Pennini ME, Chang CS, Pelletier M, Bonnell J, Koksal AC, Wu H, Dall’Acqua WF, Stover CK, Xiao X (2017) Anti-MrkA monoclonal antibodies reveal distinct structural and antigenic features of MrkA. PLoS ONE 12(1):e0170529. https://doi.org/10.1371/journal.pone.0170529
Wang-Lin SX, Zhou CG, Kamath AV, Hong K, Koppada N, Saad OM, Carrasco-Triguero M, Khojasteh C, Deng R (2018) Minimal physiologically-based pharmacokinetic modeling of DSTA4637A, A novel THIOMAB (TM) antibody antibiotic conjugate against Staphylococcus aureus, in a mouse model. MAbs 10(7):1131–1143. https://doi.org/10.1080/19420862.2018.1494478
Warrener P, Varkey R, Bonnell JC, DiGiandomenico A, Camara M, Cook K, Peng L, Zha J, Chowdury P, Sellman B, Stover CK (2014) A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models. Antimicrob Agents Chemother 58(8):4384–4391. https://doi.org/10.1128/AAC.02643-14
Yamada T (2011) Therapeutic monoclonal antibodies. Keio J Med 60(2):37–46. https://doi.org/10.2302/kjm.60.37
Yamamoto BJ, Shadiack AM, Carpenter S, Sanford D, Henning LN, Gonzales N, O’Connor E, Casey LS, Serbina NV (2016) Obiltoxaximab prevents disseminated Bacillus anthracis infection and improves survival during pre- and postexposure prophylaxis in animal models of inhalational anthrax. Antimicrob Agents Chemother 60(10):5796–5805. https://doi.org/10.1128/AAC.01102-16
Yamamoto BJ, Shadiack AM, Carpenter S, Sanford D, Henning LN, O’Connor E, Gonzales N, Mondick J, French J, Stark GV, Fisher AC, Casey LS, Serbina NV (2016) Efficacy projection of obiltoxaximab for treatment of inhalational anthrax across a range of disease severity. Antimicrob Agents Chemother 60(10):5787–5795. https://doi.org/10.1128/AAC.00972-16
Yang X, He Z, Zhang G, Lu J, Zhang H, Ren H, Tian Y, Yang H, Chen C, Li L, Fu Y, Allain JP, Li C, Wang W (2020) Evaluation of reactivity of monoclonal antibodies against Omp25 of Brucella spp. Front Cell Infect Microbiol 10:145. https://doi.org/10.3389/fcimb.2020.00145
Yang Y, Qian M, Yi S, Liu S, Li B, Yu R, Guo Q, Zhang X, Yu C, Li J, Xu J, Chen W (2016) Monoclonal antibody targeting Staphylococcus aureus surface Protein A (SasA) protect against Staphylococcus aureus sepsis and peritonitis in mice. Plos One 11(2):e0149460. https://doi.org/10.1371/journal.pone.0149460
Youssef EG, Zhang L, Alkhazraji S, Gebremariam T, Singh S, Yount NY, Yeaman MR, Uppuluri P, Ibrahim AS (2020) Monoclonal IgM antibodies targeting Candida albicans Hyr1 provide cross-kingdom protection against gram-negative bacteria. Front Immunol 11:76. https://doi.org/10.3389/fimmu.2020.00076
Zaidi TS, Zaidi T, Pier GB (2018) Antibodies to conserved surface polysaccharides protect mice against bacterial conjunctivitis. Invest Ophthalmol vis Sci 59(6):2512–2519. https://doi.org/10.1167/iovs.18-23795
Zeng H, Zhang J, Song X, Zeng J, Yuan Y, Chen Z, Xu L, Gou Q, Yang F, Zeng N, Zhang Y, Peng L, Zhao L, Zhu J, Liu Y, Luo P, Zou Q, Zhao Z (2021) An immunodominant epitope-specific monoclonal antibody cocktail improves survival in a mouse model of Staphylococcus aureus bacteremia. J Infect Dis 223(10):1743–1752. https://doi.org/10.1093/infdis/jiaa602
Zeng H, Yang F, Feng Q, Zhang J, Gu J, Jing H, Cai C, Xu L, Yang X, Xia X, Zeng N, Fan S, Zou Q (2020) Rapid and broad immune efficacy of a recombinant five-antigen vaccine against Staphylococcus aureus infection in animal models. Vaccines (Basel) 8(1):134. https://doi.org/10.3390/vaccines8010134
Zhou C, Lehar S, Gutierrez J, Rosenberger CM, Ljumanovic N, Dinoso J, Koppada N, Hong K, Baruch A, Carrasco-Triguero M, Saad O, Mariathasan S, Kamath AV (2016) Pharmacokinetics and pharmacodynamics of DSTA4637A: a novel THIOMAB antibody antibiotic conjugate against Staphylococcus aureus in mice. MAbs 8(8):1612–1619. https://doi.org/10.1080/19420862.2016.1229722
Zhou C, Cai H, Baruch A, Lewin-Koh N, Yang M, Guo F, Xu D, Deng R, Hazenbos W, Kamath AV (2019) Sustained activity of novel THIOMAB antibody-antibiotic conjugate against Staphylococcus aureus in a mouse model: longitudinal pharmacodynamic assessment by bioluminescence imaging. PLoS ONE 14(10):e0224096–e0224096. https://doi.org/10.1371/journal.pone.0224096
Zhou TT, Yue Y, Zheng F, Liang XD, Cao QX, Wang YW, Zhu J (2021) Monoclonal antibody against l-lectin module of SraP blocks adhesion and protects mice against Staphylococcus aureus challenge. J Microbiol Immunol Infect 54(3):420–428. https://doi.org/10.1016/j.jmii.2019.08.019
Zurawski DV, McLendon MK (2020) Monoclonal antibodies as an antibacterial approach against bacterial pathogens. Antibiotics (Basel) 9(4):155. https://doi.org/10.3390/antibiotics9040155
Author information
Authors and Affiliations
Contributions
All authors contributed to the study’s conception and design. Hui Wang collected the literatures and drafted the manuscript. Daijie Chen and Huili Lu revised the manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
This article does not contain any new studies with human participants or animals performed by any authors.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, H., Chen, D. & Lu, H. Anti-bacterial monoclonal antibodies: next generation therapy against superbugs. Appl Microbiol Biotechnol 106, 3957–3972 (2022). https://doi.org/10.1007/s00253-022-11989-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-022-11989-w