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

Clinical and Vaccine Immunology

Volumn 20, Issue 3, 2013, Pages 377-390

  Davies, Nicola L ^a   Compson, Joanne E ^a   MacKenzie, Brendon ^a   O'Dowd, Victoria L ^a   Oxbrow, Amanda K F ^a   Heads, James T ^a   Turner, Alison ^a   Sarkar, Kaushik ^a   Dugdale, Sarah L ^b   Jairaj, Mark ^b   Christodoulou, Louis ^c   Knight, David E O ^a   Cross, Amanda S ^a   Hervé, Karine J M ^a   Tyson, Kerry L ^a   Hailu, Hanna ^a   Doyle, Carl B ^a   Ellis, Mark ^a   Kriek, Marco ^a   Cox, Matthew ^a   Page, Matthew J T ^a   Moore, Adrian R ^a   Lightwood, Daniel J ^a   Humphreys, David P ^a   more..

^a Discovery Biology   (United Kingdom)

^b Research DMPK   (United Kingdom)

^c UCB PHARMA   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; BACTERIAL PROTEIN; BACTERIAL TOXIN; IMMUNOGLOBULIN G1 ANTIBODY; MONOCLONAL ANTIBODY; NEUTRALIZING ANTIBODY; PROTEIN TCDA; PROTEIN TCDB; TCDA ANTIBODY; TCDB ANTIBODY; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIGEN BINDING; ARTICLE; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM DIFFICILE INFECTION; CONTROLLED STUDY; DISEASE DURATION; DISEASE SEVERITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG POTENCY; DRUG SYNTHESIS; HAMSTER; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INFECTIOUS DIARRHEA; MALE; MORTALITY; NONHUMAN; PRIORITY JOURNAL; RAT; RECURRENCE RISK; SINGLE DRUG DOSE;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIBODIES, NEUTRALIZING; BACTERIAL PROTEINS; BACTERIAL TOXINS; CLOSTRIDIUM INFECTIONS; CRICETINAE; DISEASE MODELS, ANIMAL; ENTEROTOXINS; IMMUNOGLOBULIN G; IMMUNOLOGIC FACTORS; TREATMENT OUTCOME;

EID: 84875041775     PISSN: 15566811     EISSN: 1556679X     Source Type: Journal    
DOI: 10.1128/CVI.00625-12     Document Type: Article

References (60)

1. Bauer MP, Notermans DW, Van Benthem BHB, 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.
2. Wullt M, Odenholt I. 2004. A double-blind randomized controlled trial of fusidic acid and metronidazole for treatment of an initial episode of Clostridium difficile-associated diarrhoea. J. Antimicrob. Chemother. 54: 211-216.
3. Oake N, Taljaard M, Van Walraven C, Wilson K, Roth V, Forster AJ. 2010. The effect of hospital-acquired Clostridium difficile infection on inhospital mortality. Arch. Intern. Med. 170:1804-1810.
4. O'Brien JA, Lahue BJ, Caro JJ, Davidson DM. 2007. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect. Control Hosp. Epidemiol. 28:1219-1227.
5. Dubberke ER, Wertheimer AI. 2009. Review of current literature on the economic burden of Clostridium difficile infection. Infect. Control Hosp. Epidemiol. 30:57-66.
6. Forster AJ, Taljaard M, Oake N, Wilson K, Roth V, Van Walraven C. 2012. The effect of hospital-acquired infection with Clostridium difficile on length of stay in hospital. CMAJ 184:37-42.
7. 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.
8. Seal D, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M. 1987. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur. J. Clin. Microbiol. 6:51-53.
9. Shim JK, Johnson S, Samore MH, Bliss DZ, Gerding DN. 1998. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 351:633-636.
10. Lyerly DM, Saum KE, Macdonald DK, Wilkins TD. 1985. Effects of Clostridium difficile toxins given intragastrically to animals. Infect. Immun. 47:349-352.
11. Lima AAM, 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.
12. Corthier G, Muller MC, Wilkins TD, Lyerly D, L'Haridon R. 1991. Protection against experimental pseudomembranous colitis in gnotobiotic mice by use of monoclonal antibodies against Clostridium difficile toxin A. Infect. Immun. 59:1192-1195.
13. Vernet A, Corthier G, Dubos-Ramare F, Parodi AL. 1989. Relationship between levels of Clostridum difficile toxin A and toxin B and cecal lesions in gnotobiotic mice. Infect. Immun. 57:2123-2127.
14. Rothman SW, Brown JE, Diecidue A, Foret DA. 1984. Differential cytotoxic effects of toxin A and B isolated from Clostridum difficile. Infect. Immun. 46:324-331.
15. Chaves-Olarte E, Weidmann M, Von Eichel-Streiber C, Thelestam M. 1997. Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells. J. Clin. Invest. 100:1734-1741.
16. Taylor NS, Thorne GM, Bartlett JG. 1981. Comparison of two toxins produced by Clostridium difficile. Infect. Immun. 34:1036-1043.
17. Hecht G, Koutsouris A, Pothoulakis C, Lamont JT, Madara JL. 1992. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102:416-423.
18. Du T, Alfa MJ. 2004. Translocation of Clostridium difficile toxin B across polarised Caco-2 monolayers is enhanced by toxin A. Can. J. Infect. Dis. 15:83-88.
19. Savidge TC, Pan WH, Newman P, O'Brien M, Anton PM, Pothoulakis C. 2003. Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 125:413-420.
20. Nusrat A, Von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA. 2001. Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect. Immun. 69:1329-1336.
21. Flegel WA, Muller F, Daubener W, Fischer HG, Hadding U, Northoff H. 1991. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect. Immun. 59:3659-3666.
22. Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, Lamont JT, Kelly CP. 1997. IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am. J. Physiol. 273:G1333-G1340.
23. 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.
24. Kim PH, Iaconis JP, Rolfe RD. 1987. Immunization of adult hamsters against Clostridium difficile-associated ileocecitis and transfer of protection to infant hamsters. Infect. Immun. 55:2984-2992.
25. Giannasca PJ, Zhang ZX, Lei WD, Boden JA, Giel MA, Monath TP, Thomas WD. 1999. Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters. Infect. Immun. 67:527-538.
26. Kotloff KL, Wasserman SS, Losonsky GA, Thomas W, Nichols R, Edelman R, Bridwell M, Monath TP. 2001. Safety and immunogenicity of increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults. Infect. Immun. 69:988-995.
27. Sougioultzis S, Kyne L, Drudy D, Keates S, Maroo S, Pothoulakis C, Giannasca PJ, Lee CK, Warny M, Monath TP, Kelly CP. 2005. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology 128:764-770.
28. Kovaiou RD, Herndler-Brandstette D, Grubeck-Loebenstein B. 2007. Age-related changes in immunity: implications for vaccination in the elderly. Expert Rev. Mol. Med. 9:1-17.
29. Lee BY, Popovich MJ, Tian Y, Bailey RR, Ufberg PJ, Wiringa AE, Muder RR. 2010. The potential value of Clostridium difficile vaccine: an economic computer simulation model. Vaccine 28:5245-5253.
30. Lyerly DM, Bostwick EF, Binion SB, Wilkins TD. 1991. Passive immunization of hamsters against disease caused by Clostridium difficile by use of bovine immunoglobulin G concentrate. Infect. Immun. 59:2215-2218.
31. Kelly CP, Pothoulakis C, Vavva F, Castagliuolo I, Bostwick EF, O'Keane JC, Keates S, Lamont JT. 1996. Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins. Antimicrob. Agents Chemother. 40:373-379.
32. Kink JA, Williams JA. 1998. Antibodies to recombinant Clostridium difficile toxins A and B are an effective treatment and prevent relapse of C. difficile-associated disease in a hamster model of infection. Infect. Immun. 66:2018-2025.
33. Sun X, Wang H, Zhang Y, Chen K, Davis B, Feng H. 2011. Mouse relapse model of Clostridium difficile infection. Infect. Immun. 79:2856-2864.
34. Roberts A, McGlashan J, Al-Abdulla I, Ling R, Denton R, Green S, Coxon S, Landon J, Shone C. 2012. Development and evaluation of an ovine antibody-based platform for treatment of Clostridium difficile infection. Infect. Immun. 80:875-882.
35. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatring 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.
36. Demarest SJ, Hariharan M, Elia M, Salbato J, Jin P, Bird C, Short JM, Kimmel BE, Dudley M, Woodnutt G, Hansen G. 2010. Neutralization of Clostridium difficile toxin A using antibody combinations. MAbs. 2:190-198.
37. Hussack G, Arbabi-Ghahroudi M, Van Faassen H, Songer JG, Ng KKS, Mackenzie R, Tanha J. 2011. Neutralisation of Clostridium difficile toxin A with single-domain antibodies targeting the cell receptor binding domain. J. Biol. Chem. 286:8961-8976.
38. Lowy IMD, 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.
39. Lightwood D, O'Dowd V, Carrington B, Veverka V, Carr MD, Tservistas M, Henry AJ, Smith B, Tyson K, Lamour S, Sarkar K, Turner A, Lawson AD, Bourne T, Gozzard N, Palframan R. 2012. The discovery, engineering and characterisation of a highly potent anti-human IL-13 Fab fragment designed for administration by inhalation. J. Mol. Biol. 425:577-593.
40. Heads JT, Adams R, D'Hooghe LE, Page MJT, Humphreys DP, Popplewell AG, Lawson AD, Henry AJ. 2012. Relative stabilities of IgG1 and IgG4 Fab domains: influence of the light-heavy interchain disulfide bond architecture. Protein Sci. 21:1315-1322.
41. Lyerly DM, Carrig PE, Wilkins TD. 1989. Nonspecific binding of mouse monoclonal antibodies to Clostridium difficile toxins A and B. Curr. Microbiol. 19:303-306.
42. 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.
43. Ambrosino D, Babcock GJ, Broering T, Graziano R, Hernandez HJ, Lowy I, Mandell R, Molrine D, Thomas WD, Jr., Zhang HF. December 2009. Antibodies against Clostridium difficile toxins and uses thereof. US patent 7,625,559B2.
44. Garber E, Demarest SJ. 2007. A broad range of Fab stabilities within a host of therapeutic IgGs. Biochem. Biophys. Res. Commun. 355:751-757.
45. Lawley TD, Clare S, Walker AW, Stares MD, Connor TR, Raisen C, Goulding D, Rad R, Schreiber F, Brandt C, Deakin LJ, Pickard DJ, Duncan SH, Flint HJ, Clark TG, Parkhill J, Dougan G. 2012. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8:e1002995. doi:10.1371/journal.ppat. 1002995.
46. Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A, Viale A, Ubeda C, Xavier J, Pamer EG. 2012. Profound alteration of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile colitis. Infect. Immun. 80:62-73.
47. Steele J, Chen K, Sun X, Zhang Y, Wang H, Tzipori S, Feng H. 2012. Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models. J. Infect. Dis. 205:384-391.
48. Mitchell TJ, Ketley JM, Haslam SC, Stephen J, Burdon DW, Candy DCA, Daniel R. 1986. Effect of toxin A and B of Clostridium difficile on rabbit ileum and colon. Gut 27:78-85.
49. Wu AL, Walker WA. 1976. Immunological control mechanism against cholera toxin: interference with toxin binding to intestinal cells. Infect. Immun. 14:1034-1042.
50. Walker WA, Isselbacher KJ, Bloch KJ. 1973. Intestinal uptake of macromolecules. II. Effect of parenteral immunization. J. Immunol. 111:221-226.
51. Yousaf N, Howard JC, Williams BD. 1986. Studies in cobra venom factor treated rats of antibody coated erythrocyte clearance by the spleen: differential influence of red blood cell antigen number on the inhibitory effects of immune complexes on Fc dependent clearance. Clin. Exp. Immunol. 66:654-660.
52. Davies KA, Hird V, Stewart S, Sivolapenko GB, Jose P, Epenetos AA, Walport MJ. 1990. A study of in vivo immune complex formation and clearance in man. J. Immunol. 144:4613-4620.
53. Mannik M, Arend WP, Hall AP, Gilliland BC. 1971. Studies on antigenantibody complexes. J. Exp. Med. 133:713-719.
54. Jacob SS, Sebastian JC, Hiorns D, Jacob S, Mukerjee PK. 2004. Clostridium difficile and acute respiratory distress syndrome. Heart Lung 33:265-268.
55. Steele J, Feng H, Parry N, Tzipori S. 2010. Piglet models of acute or chronic Clostridium difficile illness. J. Infect. Dis. 201:428-434.
56. Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, Claypool SM, Kaser A, Nagaishi T, Higgins DE, Mizoguchi E, Wakatsuki Y, Roopenian DC, Mizoguchi A, Lencer WI, Blumberg RS. 2006. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J. Clin. Invest. 116:2142-2151.
57. Xu DZ, Huang KL, Zhao K, Xu LF, Shi N, Yuan ZH, Wen YM. 2005. Vaccination with recombinant HBsAg-HBIG complex in healthy adults. Vaccine 23:2658-2664
58. Ye L, Zeng R, Bai Y, Roopenian DC, Zhu X. 2011. Efficient mucosal vaccination mediated by the neonatal Fc receptor. Nat. Biotechnol. 29: 158-163.
59. Sanna PP, Ramiro-Ibanez F, De Logu D. 2000. Synergistic interactions of antibodies in rate of virus neutralisation. Virology 270:386-396.
60. Riegler M, Sedivy R, Pothoulakis C, Hamilton G, Zacheri J, Bischof G, Cosentini E, Feil W, Schiessel R, Lamont JT, Wenzl E. 1995. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J. Clin. Invest. 95:2004-2011. 61. Leav BA, Blair B, Leney M, Knauber M, Reilly C, Lowy I, Gerding DN, Kelly CP, Katchar K, Baxter R, Ambrosino D, Molrine D. 2010. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine 28:965-969.