Novel clostridium difficile anti- Toxin (TcdA and TcdB) humanized monoclonal antibodies demonstrate in vitro neutralization across a broad spectrum of clinical strains and in vivo potency in a hamster spore challenge model

PLoS ONE

Volumn 11, Issue 6, 2016, Pages

  Qiu, Hongyu ^a   Cassan, Robyn ^a   Johnstone, Darrell ^a   Han, Xiaobing ^a   Joyee, Antony George ^a   McQuoid, Monica ^a   Masi, Andrea ^a   Merluza, John ^a   Hrehorak, Bryce ^a   Reid, Ross ^a   Kennedy, Kieron ^a   Tighe, Bonnie ^a   Rak, Carla ^a   Leonhardt, Melanie ^a   Dupas, Brian ^a   Saward, Laura ^a   Berry, Jody D ^b   Nykiforuk, Cory L ^a  

^a Emergent Biosolutions   (Canada)

^b Grifols   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTITOXIN; CANMABA4 ANTIBODY; CANMABB1 ANTIBODY; CANMABB4 ANTIBODY; MONOCLONAL ANTIBODY; UNCLASSIFIED DRUG; BACTERIAL PROTEIN; BACTERIAL TOXIN; BACTERIUM ANTIBODY; ENTEROTOXIN; IMMUNOGLOBULIN G; NEUTRALIZING ANTIBODY; TCDA PROTEIN, CLOSTRIDIUM DIFFICILE; TOXB PROTEIN, CLOSTRIDIUM DIFFICILE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BACTERIAL STRAIN; CLOSTRIDIUM DIFFICILE INFECTION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; EC50; IN VITRO STUDY; IN VIVO STUDY; INFECTION PREVENTION; NONHUMAN; PEPTOCLOSTRIDIUM DIFFICILE; PROTEIN EXPRESSION; SURVIVAL; SURVIVAL RATE; SYRIAN HAMSTER; ANIMAL; BACTERIAL SPORE; CLOSTRIDIUM INFECTION; DISEASE MODEL; HAMSTER; HUMAN; IMMUNOLOGY; ISOLATION AND PURIFICATION; MICROBIOLOGY; MORTALITY; MOUSE; SERODIAGNOSIS;

ANIMALS; ANTIBODIES, BACTERIAL; ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTIBODIES, NEUTRALIZING; ANTITOXINS; BACTERIAL PROTEINS; BACTERIAL TOXINS; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; CRICETINAE; DISEASE MODELS, ANIMAL; ENTEROTOXINS; HUMANS; IMMUNOGLOBULIN G; MICE; NEUTRALIZATION TESTS; SPORES, BACTERIAL;

EID: 84976543742     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0157970     Document Type: Article

References (70)

1. Aslam S, Hamill RJ, Musher DM (2005) Treatment of Clostridium difficile- Associated disease: old therapies and new strategies. Lancet Infect Dis 5: 549-557. PMID: 16122678.
2. Ananthakrishnan AN (2011) Clostridium difficile infection: Epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol 8: 17-26. doi: 10.1038/nrgastro.2010.190 PMID: 21119612.
3. Lucado J, Gould C, Elixhauser A (2006) Clostridium Difficile Infections (CDI) in hospital stays, 2009: Statistical Brief #124. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs 1-12.
4. Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, et al. (2011) Clostridium difficile infection in Europe: A hospital-based survey. Lancet 377: 63-73. doi: 10.1016/S0140-6736 (10)61266-4 PMID: 21084111.
5. Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J Jr. (1995) Clostridium difficile- Associated diarrhea and colitis. Infect Control Hosp Epidemiol 16: 459-477. PMID: 7594392.
6. Salkind AR (2010) Clostridium difficile: An update for the primary care clinician. South Med J 103: 896- 902. doi: 10.1097/SMJ.0b013e3181eab419 PMID: 20697321.
7. Kee VR (2012) Clostridium difficile infection in older adults: A review and update on its management. Am J Geriatr Pharmacother 10: 14-24. doi: 10.1016/j.amjopharm.2011.12.004 PMID: 22260856.
8. Blondeau JM (2009) What have we learned about antimicrobial use and the risks for Clostridium difficile- Associated diarrhoea? J Antimicrob Chemother 63: 238-242. doi: 10.1093/jac/dkn477 PMID: 19028718.
9. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. (2013) Guidelines for diagnosis, treatment, and prevention of Clostridium difficile Infections. Am J Gastroenterol 108: 478-498. doi: 10.1038/ajg.2013.4 PMID: 23439232.
10. Marsh JW, Arora R, Schlackman JL, Shutt KA, Curry SR, Harrison LH (2012) Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol 50: 4078-4082. doi: 10.1128/JCM. 02291-12 PMID: 23052318.
11. Pepin J, Valiquette L, Gagnon S, Routhier S, Brazeau I (2007) Outcomes of Clostridium difficile- Associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Am J Gastroenterol 102: 2781-2788. PMID: 17900327.
12. Akerlund T, Persson I, Unemo M, Noren T, Svenungsson B, Wullt M, Burman LG (2008) Increased sporulation rate of epidemic Clostridium difficile Type 027/NAP1. J Clin Microbiol 46: 1530-1533. doi: 10.1128/JCM.01964-07 PMID: 18287318.
13. Freeman J, Bauer MP, Baines SD, Corver J, Fawley WN, Goorhuis B, et al. (2010) The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 23: 529-549. doi: 10.1128/CMR.00082-09 PMID: 20610822.
14. Viswanathan VK, Mallozzi MJ, Vedantam G (2010) Clostridium difficile infection: An overview of the disease and its pathogenesis, epidemiology and interventions. Gut Microbes 1: 234-242. PMID: 21327030.
15. Mattila E, Uusitalo-Seppala R, Wuorela M, Lehtola L, Nurmi H, Ristikankare M, Moilanen V, et al. (2012) Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 142: 490-496. doi: 10.1053/j.gastro.2011.11.037 PMID: 22155369.
16. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, et al. (2010) Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362: 197-205. doi: 10.1056/NEJMoa0907635 PMID: 20089970.
17. Wilcox MH (2004) Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 53: 882-884. PMID: 15073160.
18. Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, et al. (2005) Clostridium difficile toxoid vaccine in recurrent C. difficile- Associated diarrhea. Gastroenterology 128: 764-770. PMID: 15765411.
19. Gerding DN, Johnson S (2010) Management of Clostridium difficile infection: Thinking inside and outside the box. Clin Infect Dis 51: 1306-1313. doi: 10.1086/657116 PMID: 20979491.
20. Brandt LJ, Aroniadis OC (2013) An overview of fecal microbiota transplantation: Techniques, indications, and outcomes. Gastrointest Endosc 78: 240-249. doi: 10.1016/j.gie.2013.03.1329 PMID: 23642791.
21. van NE, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368: 407-415. doi: 10.1056/NEJMoa1205037 PMID: 23323867.
22. Voth DE, Ballard JD (2005) Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18: 247-263. PMID: 15831824.
23. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB (2010) Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A 107: 13467-13472. doi: 10. 1073/pnas.1002199107 PMID: 20624955.
24. Albesa-Jové D, Bertrand T, Carpenter EP, Swain GV, Lim J, Zhang J, et al. (2010) Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS. JMol Biol 396: 1260-1270.
25. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N, et al. (2006) Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun 74: 6339-6347. IAI. PMID: 16966409.
26. Ho JG, Greco A, Rupnik M, Ng KK (2005) Crystal structure of receptor-binding C- Terminal repeats from Clostridium difficile toxin A. Proc Natl Acad Sci U S A 102: 18373-18378. PMID: 16344467.
27. Marozsan AJ, Ma D, Nagashima KA, Kennedy BJ, Kang YK, Arrigale RR, et al. (2012) Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. J Infect Dis 206: 706-713. doi: 10.1093/infdis/jis416 PMID: 22732923.
28. Mathieu R, Lim J, Simpson P, Prasannan S, Fairweather N, Matthews S (2003) Resonance assignment and topology of a clostridial repetitive oligopeptide (CROP) region of toxin A from Clostridium difficile. J Biomol NMR 25: 83-84. PMID: 12567004.
29. Lima AA, Lyerly DM, Wilkins TD, Innes DJ, Guerrant RL (1988) Effects of Clostridium difficile toxins A and B in rabbit small and large intestine in vivo and on cultured cells in vitro. Infect Immun 56: 582-588. PMID: 3343050.
30. Shen A (2012) Clostridium difficile Toxins: mediators of iInflammation. J Innate Immun 4: 149-158. doi: 10.1159/000332946 PMID: 22237401.
31. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP (2010) The role of toxin A and toxin B in Clostridium difficile infection. Nature 467: 711-713. doi: 10.1038/nature09397 PMID: 20844489.
32. Carter GP, Chakravorty A, Pham Nguyen TA, Mileto S, Schreiber F, Li L, et al. (2015) Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile Infections. mBio 6: E00551-15. doi: 10.1128/mBio.00551-15 PMID: 26037121.
33. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, et al. (2009) Toxin B is essential for virulence of Clostridium difficile. Nature 458: 1176-1179. doi: 10.1038/nature07822 PMID: 19252482.
34. Steele J, Mukherjee J, Parry N, Tzipori S (2013) Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridium difficile disease. J Infect Dis 207: 323-330. doi: 10.1093/infdis/jis669 PMID: 23125448.
35. Davies NL, Compson JE, Mackenzie B, O'Dowd VL, Oxbrow AK, Heads JT, et al. (2013) A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin Vaccine Immunol 20: 377-390. doi: 10.1128/CVI.00625-12 PMID: 23324518.
36. Giannasca PJ, Zhang ZX, Lei WD, Boden JA, Giel MA, Monath TP, et al. (1999) Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters. Infect Immun 67: 527-538. PMID: 9916055.
37. Anosova NG, Cole LE, Li L, Zhang J, Brown AM, Mundle S, et al. (2015) A Combination of three fully human toxin A- And toxin B-specific monoclonal antibodies rotects against challenge with highly virulent epidemic strains of Clostridium difficile in the hamster model. Clin Vaccine Immunol 22: 711-725. doi: 10.1128/CVI.00763-14 PMID: 25924765.
38. Gerding DN et al. (2015) Phase 3 double-blind study of actoxumab & bezlotoxumab for prevention of recurrent C. difficile infection in patients on standard of care antibiotics (MODIFY II).
39. Wilcox M et al. (2015) Phase 3 double-blind study of actoxumab & bezlotoxumab for prevention of recurrent C. difficile infection in patients on standard of care antibiotics (MODIFY I).
40. Cassan R, Berry J, Johnstone D, Toth D (2013) Clostridium difficile antibodies. Patent WO2013028810A1.
41. Cassan R, Johnstone D, Saward L, George JA, Berry J (2015) Antibodies against clostridium difficile. Patent WO2014085749A3.
42. Hu MY, Katchar K, Kyne L, Maroo S, Tummala S, Dreisbach V, et al. (2009) Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology 136: 1206-1214. doi: 10.1053/j.gastro.2008.12.038 PMID: 19162027.
43. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. (2010) Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 31: 431-455. doi: 10.1086/651706 PMID: 20307191.
44. Gravel D, Miller M, Simor A, Taylor G, Gardam M, McGeer A, et al. (2009) Health care- Associated Clostridium difficile infection in adults admitted to acute care Hospitals in Canada: A Canadian nosocomial infection surveillance program study. Clin Infect Dis 48: 568-576. doi: 10.1086/596703 PMID: 19191641.
45. Kaslow DC, Shiver JW (2011) Clostridium difficile and methicillin-resistant Staphylococcus aureus: Emerging concepts in vaccine development. Annu Rev Med 62: 201-215. doi: 10.1146/annurev-med- 051109-101544 PMID: 20707676.
46. Leuzzi R, Spencer J, Buckley A, Brettoni C, Martinelli M, Tulli L, et al. (2013) Protective efficacy induced by recombinant Clostridium difficile toxin fragments. Infect Immun 81: 2851-2860. doi: 10.1128/IAI. 01341-12 PMID: 23716610.
47. Libby JM, Wilkins TD (1982) Production of antitoxins to two toxins of Clostridium difficile and immunological comparison of the toxins by cross-neutralization studies. Infect Immun 35: 374-376. PMID: 6172384.
48. Chow S-K, Casadevall A (2012) Monoclonal antibodies and toxins-A perspective on function and isotype. toxins 4: 430-454. doi: 10.3390/toxins4060430 PMID: 22822456.
49. Hussack G, Arbabi-Ghahroudi M, van Faassen H, Songer JG, Ng KKS, MacKenzie R, Tanha J (2011) Neutralization of Clostridium difficile toxin A with single-domain antibodies targeting the cell receptor binding domain. J Biol Chem 286: 8961-8976. doi: 10.1074/jbc.M110.198754 PMID: 21216961.
50. Foglia G, Shah S, Luxemburger C, Pietrobon PJF (2012) Clostridium difficile: Development of a novel candidate vaccine. Vaccine 30: 4307-4309. doi: 10.1016/j.vaccine.2012.01.056 PMID: 22682287.
51. Kyne L, Warny M, Qamar A, Kelly CP (2000) Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 342: 390-397. PMID: 10666429.
52. Leav BA, Blair B, Leney M, Knauber M, Reilly C, Lowy I, et al. (2010) Serum anti- Toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine 28: 965-969. doi: 10. 1016/j.vaccine.2009.10.144 PMID: 19941990.
53. Loo VG, Bourgault AM, Poirier L, Lamothe F, Michaud S, Turgeon N, et al. (2011) Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 365: 1693-1703. doi: 10.1056/NEJMoa1012413 PMID: 22047560.
54. Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, et al. (2014) A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis 210: 964-972. doi: 10.1093/infdis/jiu196 PMID: 24683195.
55. Demarest SJ, Hariharan M, Elia M, Salbato J, Jin P, Bird C, Short JM, et al. (2010) Neutralization of Clostridium difficile toxin A using antibody combinations. MAbs 2: 190-198. PMID: 20150758.
56. Hussack G, Tanha J (2010) Toxin-Specific Antibodies for the treatment of Clostridium difficile: current status and future perspectives. Toxins (Basel) 2: 998-1018.
57. Loisel S, Ohresser M, Pallardy M, Daydé D, Berthou C, Cartron G, et al. (2007) Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit Rev Oncol Hematol 62: 34-42. PMID: 17197192.
58. Overdijk MB, Verploegen S, Ortiz Buijsse A, Vink T, Leusen JHW, Bleeker WK, et al. (2012) Crosstalk between human IgG isotypes and murine effector cells. J Immunol 189: 3430-3438. PMID: 22956577.
59. Rupnik M (2009) Clostridium difficile toxinotyping. In: Mullany P, Roberts AP (Eds.), Clostridium difficile. Springer Protocols. New York, pp. 67-76.
60. Stabler RA, Dawson LF, Phua LTH, Wren BW (2008) Comparative analysis of BI/NAP1/027 hypervirulent strains reveals novel toxin B-encoding gene (tcdB) sequences. J Med Microbiol 57: 771-775. doi: 10.1099/jmm.0.47743-0 PMID: 18480336.
61. Ke N, Wang X, Xu X, Abassi Y (2011) The xCELLigence system for real-Time and label-free monitoring of cell viability. In: Stoddart MJ (Eds.). Mammalian Cell Viability. Humana Press. New York, pp. 33-43.
62. Babcock GJ, Thomas WD, Broering TJ (2005) Human monoclonal antibodies neutralize toxins produced by epidemic strains of Clostridium difficile. 43rd Annual Meeting of the Infectious Disease Society of America, Abstract 164, San Francisco, CA, 6-9 October.
63. Lanis JM, Barua S, Ballard JD (2010) Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathog 6: E1001061. doi: 10.1371/journal.ppat.1001061 PMID: 20808849.
64. Chaves-Olarte E, Low P, Freer E, Norlin T, Weidmann M, von Eichel-Streiber C, et al. (1999) A novel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins. J Biol Chem 274: 11046-11052. PMID: 10196187.
65. Huelsenbeck J, Dreger S, Gerhard R, Barth H, Just I, Genth H (2007) Difference in the cytotoxic effects of toxin B from Clostridium difficile strain VPI 10463 and toxin B from variant Clostridium difficile strain 1470. Infect Immun 75: 801-809. PMID: 17145947.
66. Sambol SP, Merrigan MM, Lyerly D, Gerding DN, Johnson S (2000) Toxin gene analysis of a variant strain of Clostridium difficile that causes human clinical disease. Infect Immun 68: 5480-5487. PMID: 10992443.
67. Yang G, Zhou B, Wang J, He X, Sun X, Nie W, et al. (2008) Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium. BMC Microbiol 8: 192 doi: 10.1186/1471-2180-8-192 PMID: 18990232.
68. Burger S, Tatge H, Hofmann F, Genth H, Just I, Gerhard R (2003) Expression of recombinant Clostridium difficile toxin A using the Bacillus megaterium system. Biochem Biophys Res Commun 307: 584- 588. PMID: 12893263.
69. Sorg JA, Dineen SS (2005) Laboratory Maintenance of Clostridium difficile. In: Current Protocols in Microbiology. John Wiley & Sons, Inc. New Jersey.
70. Abdiche YN, Miles A, Eckman J, Foletti D, Van Blarcom TJ, Yeung YA, et al. (2014) High- Throughput epitope binning assays on label-free array-based biosensors can yield exquisite epitope discrimination that facilitates the selection of monoclonal antibodies with functional activity. PLoS ONE 9: E92451. doi: 10.1371/journal.pone.0092451 PMID: 24651868.