Broad coverage of genetically diverse strains of clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling

Antimicrobial Agents and Chemotherapy

Volumn 59, Issue 2, 2015, Pages 1052-1060

  Hernandez, Lorraine D ^a   Racine, Fred ^a   Xiao, Li ^a   DiNunzio, Edward ^a   Hairston, Nichelle ^a   Sheth, Payal R ^a   Murgolo, Nicholas J ^a   Therien, Alex G ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTOXUMAB; BACTERIAL TOXIN; BEZLOTOXUMAB; EPITOPE; ANTIINFECTIVE AGENT; BACTERIAL PROTEIN; MONOCLONAL ANTIBODY;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANTIBODY BLOOD LEVEL; ANTIGEN BINDING; ARTICLE; BACTERIAL GENETICS; BACTERIAL STRAIN; BACTERIUM ISOLATE; BINDING AFFINITY; CELL COUNT; CRYSTAL STRUCTURE; CYTOTOXICITY; DRUG POTENCY; DRUG RECEPTOR BINDING; ENZYME LINKED IMMUNOSORBENT ASSAY; GENETIC VARIABILITY; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; PEPTOCLOSTRIDIUM DIFFICILE; PRIORITY JOURNAL; SUPERNATANT; SURFACE PLASMON RESONANCE; VERO CELL LINE; CELL LINE; CLINICAL TRIAL; CLOSTRIDIUM INFECTIONS; DRUG EFFECTS; FEMALE; GENETICS; HUMAN; IMMUNOLOGY; MALE; MICROBIOLOGY; PATHOGENICITY; PHASE 2 CLINICAL TRIAL;

ANTI-BACTERIAL AGENTS; ANTIBODIES, MONOCLONAL; BACTERIAL PROTEINS; CELL LINE; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; EPITOPES; FEMALE; HUMANS; MALE;

EID: 84921762273     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.04433-14     Document Type: Article

References (23)

1. Bassetti M, Villa G, Pecori D, Arzese A, Wilcox M. 2012. Epidemiology, diagnosis and treatment of Clostridium difficile infection. Expert Rev Anti Infect Ther 10:1405-1423. http://dx.doi.org/10.1586/eri.12.135.
2. Rupnik M, Wilcox MH, Gerding DN. 2009. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7:526-536. http://dx.doi.org/10.1038/nrmicro2164.
3. Carter GP, Rood JI, Lyras D. 2012. The role of toxin A and toxin B in the virulence of Clostridium difficile. Trends Microbiol 20:21-29. http://dx .doi.org/10.1016/j.tim.2011.11.003.
4. Pruitt RN, Lacy DB. 2012. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol 2:28. http://dx .doi.org/10.3389/fcimb.2012.00028.
5. Shen A. 2012. Clostridium difficile toxins: mediators of inflammation. J Innate Immun 4:149-158. http://dx.doi.org/10.1159/000332946.
6. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N, Stack AM, Lowy I, Graziano R, Molrine D, Ambrosino DM, Thomas WD, Jr. 2006. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun 74:6339-6347. http://dx.doi.org/10.1128/IAI .00982-06.
7. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD, Jr, Leney M, Sloan S, Hay CA, Ambrosino DM. 2010. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362:197-205. http://dx.doi.org/10.1056/NEJMoa0907635.
8. 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 289:18008-18021. http://dx.doi.org/10.1074/jbc.M114.560748.
9. McDonald LC, Killgore GE, Thompson A, Owens RC, Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN. 2005. An epidemic, toxin genevariant strain of Clostridium difficile. N Engl J Med 353:2433-2441. http: //dx.doi.org/10.1056/NEJMoa051590.
10. O'Connor JR, Johnson S, Gerding DN. 2009. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology 136: 1913-1924. http://dx.doi.org/10.1053/j.gastro.2009.02.073.
11. Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, Monnet DL, van Dissel JT, Kuijper EJ. 2011. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 377:63-73. http://dx.doi.org/10.1016/S0140-6736(10)61266-4.
12. Manzo CE, Merrigan MM, Johnson S, Gerding DN, Riley TV, Silva J, Jr, Brazier JS. 2014. International typing study of Clostridium difficile. Anaerobe 28:4-7. http://dx.doi.org/10.1016/j.anaerobe.2014.04.005.
13. Rupnik M. 2008. Heterogeneity of large clostridial toxins: importance of Clostridium difficile toxinotypes. FEMS Microbiol Rev 32:541-555. http: //dx.doi.org/10.1111/j.1574-6976.2008.00110.x.
14. Friguet B, Chaffotte AF, Djavadi-Ohaniance L, Goldberg ME. 1985. Measurements of the true affinity constant in solution of antigenantibody complexes by enzyme-linked immunosorbent assay. J Immunol Methods 77:305-319. http://dx.doi.org/10.1016/0022-1759(85)90044-4.
15. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. 1990. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82: 1107-1112. http://dx.doi.org/10.1093/jnci/82.13.1107.
16. Torres J, Camorlinga-Ponce M, Munoz O. 1992. Sensitivity in culture of epithelial cells from rhesus monkey kidney and human colon carcinoma to toxins A and B from Clostridium difficile. Toxicon 30:419-426. http: //dx.doi.org/10.1016/0041-0101(92)90538-G.
17. Borriello SP, Wren BW, Hyde S, Seddon SV, Sibbons P, Krishna MM, Tabaqchali S, Manek S, Price AB. 1992. Molecular, immunological, and biological characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile. Infect Immun 60:4192-4199.
18. Kato H, Kato H, Ito Y, Akahane T, Izumida S, Yokoyama T, Kaji C, Arakawa Y. 2010. Typing of Clostridium difficile isolates endemic in Japan by sequencing of slpA and its application to direct typing. J Med Microbiol 59:556-562. http://dx.doi.org/10.1099/jmm.0.016147-0.
19. Walker AS, Eyre DW, Wyllie DH, Dingle KE, Griffiths D, Shine B, Oakley S, O'Connor L, Finney J, Vaughan A, Crook DW, Wilcox MH, Peto TE. 2013. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis 56: 1589-1600. http://dx.doi.org/10.1093/cid/cit127.
20. Davies NL, Compson JE, Mackenzie B, O'Dowd VL, Oxbrow AK, Heads JT, Turner A, Sarkar K, Dugdale SL, Jairaj M, Christodoulou L, Knight DE, Cross AS, Herve KJ, Tyson KL, Hailu H, Doyle CB, Ellis M, Kriek M, Cox M, Page MJ, Moore AR, Lightwood DJ, Humphreys DP. 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. http://dx .doi.org/10.1128/CVI.00625-12.
21. Marozsan AJ, Ma D, Nagashima KA, Kennedy BJ, Kang YK, Arrigale RR, Donovan GP, Magargal WW, Maddon PJ, Olson WC. 2012. Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. J Infect Dis 206:706-713. http://dx.doi .org/10.1093/infdis/jis416.
22. 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. http://dx.doi.org/10 .1093/infdis/jis669.
23. Yang Z, Ramsey J, Hamza T, Zhang Y, Li S, Yfantis HG, Lee D, Hernandez LD, Seghezzi W, Furneisen JM, Davis NM, Therien AG, Feng H. 2015. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun 83:822-831. http://dx.doi.org/10.1128/IAI .02897-14.