Article thumbnail

Toxin-Specific Antibodies for the Treatment of Clostridium difficile: Current Status and Future Perspectives †

By Greg Hussack and Jamshid Tanha

Abstract

Therapeutic agents targeting bacterial virulence factors are gaining interest as non-antibiotic alternatives for the treatment of infectious diseases. Clostridium difficile is a Gram-positive pathogen that produces two primary virulence factors, enterotoxins A and B (TcdA and TcdB), which are responsible for Clostridium difficile-associated disease (CDAD) and are targets for CDAD therapy. Antibodies specific for TcdA and TcdB have been shown to effectively treat CDAD and prevent disease relapse in animal models and in humans. This review summarizes the various toxin-specific antibody formats and strategies under development, and discusses future directions for CDAD immunotherapy, including the use of engineered antibody fragments with robust biophysical properties for systemic and oral delivery

Topics: Review
Publisher: MDPI
OAI identifier: oai:pubmedcentral.nih.gov:3153223
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2010). A bispecific antibody to provide full protection against lethal scorpion envenoming.
  2. (2009). A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. Vaccine
  3. (2007). A novel pentamer versus pentamer approach to generating neutralizers of verotoxin 1.
  4. (2009). a promising tool for species-specific diagnosis of Taenia solium cysticercosis.
  5. (2008). A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial.
  6. (2004). Active and passive immunization against Clostridium difficile diarrhea and colitis. Vaccine
  7. (2008). Active immunization of hamsters against Clostridium difficile infection using surface-layer protein.
  8. (2004). Aggregation-resistant domain antibodies selected on phage by heat denaturation.
  9. (2005). An epidemic, toxin gene-variant strain of Clostridium
  10. (1996). Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins. Antimicrob. Agents Chemother.
  11. Anti-virulence strategies to combat bacteria-mediated disease.
  12. (2008). Antibodies for the treatment of bacterial infections: current experience and future prospects.
  13. (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.
  14. (2006). Antibody repertoire development in camelids.
  15. (2006). Antibody repertoire development in cartilaginous fish.
  16. (2001). Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet
  17. (2007). Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity.
  18. (2007). Autocatalytic cleavage of Clostridium difficile toxin B. Nature
  19. (1989). Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli.
  20. (2002). Binding of Clostridium difficile surface layer proteins to gastrointestinal tissues.
  21. (2008). bivalent domains and chimeric heavy chain-only antibodies with high neutralizing efficacy for scorpion toxin AahI’.
  22. (2005). Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile-associated diarrhoea: preclinical and preliminary clinical data.
  23. (1999). Bovine immunoglobulin concentrate-Clostridium difficile retains C. difficile toxin neutralising activity after passage through the human stomach and small intestine. Gut
  24. (2006). Carbohydrate recognition by Clostridium difficile toxin
  25. (1986). Cell surface binding site for Clostridium difficile enterotoxin: evidence for a glycoconjugate containing the sequence Gal alpha 1–3Gal beta
  26. (1989). Characterization of protective antibodies in hamsters immunized against C. difficile toxins A
  27. (1986). Characterization of toxins A and B of Clostridium difficile with monoclonal antibodies.
  28. (2007). Clinical outcomes of intravenous immune globulin in severe Clostridium difficile-associated diarrhea.
  29. (2009). Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology
  30. Clostridium difficile infection: New developments in epidemiology and pathogenesis.
  31. (1992). Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology
  32. (2005). Clostridium difficile toxins: mechanism of action and role in disease.
  33. (2005). Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology
  34. (2007). Clostridium difficile-associated diarrhoea: bovine anti-Clostridium difficile whey protein to help aid the prevention of relapses. Gut
  35. (2009). Clostridium difficile: controversies and approaches to management.
  36. (2004). Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrent Clostridium difficile associated diarrhoea.
  37. (1996). Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme.
  38. (2010). Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A.
  39. (2004). Crystal structure of the shark singledomain antibody V region in complex with lysozyme. Science
  40. (2004). Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea.
  41. (2003). Domain antibodies: proteins for therapy. Trends Biotechnol.
  42. (1985). Effects of Clostridium difficile toxins given intragastrically to animals.
  43. (2000). Effects of Clostridium difficile toxins on epithelial cell
  44. (2004). Efficient cancer therapy with a nanobody-based conjugate. Cancer Res.
  45. (2004). Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies. African trypanosomes as paradigm.
  46. (2005). Engineered antibody fragments and the rise of single domains.
  47. (2009). Enhancement of toxin- and virus-neutralizing capacity of single-domain antibody fragments by N-glycosylation.
  48. (2007). Exploring the capacity of minimalist protein interfaces: interface energetics and affinity maturation to Toxins 2010, 2 picomolar KD of a single-domain antibody with a flat paratope.
  49. (2001). Expression of single-chain Fv-Fc fusions in Pichia pastoris.
  50. (2010). Fidaxomicin: a macrocyclic antibiotic for the management of Clostridium difficile infection.
  51. (2010). Four distinct structural domains in Clostridium difficile toxin B visualized using
  52. (2008). Functional properties of the carboxy-terminal host cell-binding domains of the two toxins, TcdA and TcdB, expressed by Clostridium difficile. Glycobiology
  53. (1995). Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature
  54. (1994). Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection.
  55. (1992). Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding. Gastroenterology
  56. (2006). Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters.
  57. (2009). Identification of potent nanobodies to neutralize the most poisonous polypeptide from scorpion venom.
  58. (1987). Immunization of adult hamsters against Clostridium difficile-associated ileocecitis and transfer of protection to infant hamsters.
  59. (2010). In situ delivery of passive immunity by lactobacilli producing single-chain antibodies.
  60. (2002). Intravenous immunoglobulin for recurrent Clostridium difficile diarrheoea. Gut
  61. (2006). Intravenous immunoglobulin for resistant Clostridium difficile infection. Age Ageing
  62. Intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis: an observational study and review of the literature.
  63. (2006). Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis. Colon Rectum
  64. (2008). Intravenous immunoglobulin therapy for refractory Clostridium difficile toxin colitis in chronic kidney disease: case reports and literature review. NDT Plus
  65. (1997). Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut
  66. (2005). Isolation of monomeric human V(H)s by a phage selection.
  67. (2006). Lactobacilli expressing variable domain of llama heavy-chain antibody fragments (lactobodies) confer protection against rotavirus-induced diarrhea.
  68. (2008). Llama antibody fragments with cross-subtype human immunodeficiency virus type 1 (HIV-1)-neutralizing properties and high affinity for HIV-1 gp120.
  69. (2008). Llama-derived single-chain antibody fragments directed to rotavirus VP6 protein possess broad neutralizing activity in vitro and confer protection against diarrhea in
  70. (2005). LuxS/autoinducer-2 quorum sensing molecule regulates transcriptional virulence gene expression in Clostridium difficile.
  71. (2005). Metronidazole for Clostridium difficile-associated disease: is it okay for Mom?
  72. (2006). Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies.
  73. (1992). Multiple relapses of Clostridium difficile-associated diarrhea in a cancer patient. Successful control with long-term cholestyramine therapy.
  74. (1993). Naturally occurring antibodies devoid of light chains.
  75. (2006). Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.
  76. Neutralization of Clostridium difficile toxin A using antibody combinations. MAbs 2010, 2, [Epub ahead of print].
  77. (2006). Nitazoxanide for the treatment of Clostridium difficile colitis.
  78. (1993). Oral immunoglobulin A supplement in treatment of Clostridium difficile enteritis. Lancet
  79. (2009). Passive immunization llama single-domain antibody fragments reduces foot-and-mouth disease transmission between pigs. Vaccine
  80. (1991). Passive immunization of hamsters against disease caused by Clostridium difficile by use of bovine immunoglobulin G concentrate.
  81. (2009). Pentabody-mediated antigen delivery induces antigen-specific mucosal immune response.
  82. (2002). Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.
  83. (1979). Prevention of clindamycin-induced colitis in hamsters by Clostridium sordellii antitoxin. Gastroenterology
  84. (2009). Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systemic review.
  85. (2009). Probiotics as prevention and treatment for diarrhea.
  86. (2009). Production of chimeric heavy-chain antibodies.
  87. (1991). Production of monoclonal antibody to Clostridium difficile toxin A which neutralizes enterotoxicity but not haemagglutination activity.
  88. (2007). production, and applications of camelid singledomain antibody fragments.
  89. (1991). Protection against experimental pseudomembranous colitis in gnotobiotic mice by use of monoclonal antibodies against Clostridium difficile toxin
  90. (2005). Ramoplanin: a lipoglycodepsipeptide antibiotic.
  91. (2002). Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrob. Agents Chemother.
  92. (2003). Recombinant single-chain variable fragment antibodies directed against Clostridium difficile toxin B produced by use of an optimized phage display system.
  93. (2003). Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube.
  94. (2009). Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes.
  95. (2006). Reduction in morbidity of rotavirus induced diarrhoea in mice by yeast produced monovalent llama-derived antibody fragments. Vaccine
  96. (2007). Rho-glucosylating Clostridium difficile toxins A and B: new structural insights into structure and function. Glycobiology
  97. (2008). Rifamycin antibiotics for treatment of Clostridium difficile-associated
  98. (2005). Selecting and screening recombinant antibody libraries.
  99. (1997). Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett.
  100. (2006). Selection and optimization of proteolytically stable llama single-domain antibody fragments for oral immunotherapy.
  101. (1995). Selective neutralization of a bacterial enterotoxin by serum immunoglobulin A in response to mucosal disease.
  102. (1983). Serum antibody response to toxins A and B of Clostridium difficile.
  103. (1999). Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters.
  104. (2004). Single domain antibodies derived from dromedary lymph node and peripheral blood lymphocytes sensing conformational variants of prostate-specific antigen.
  105. (2007). Single domain antibodies from llama effectively and specifically block T cell ecto-ADP-ribosyltransferase ART2.2 in vivo.
  106. (2009). Single domain antibodies: promising experimental and therapeutic tools in infection and immunity.
  107. (2009). Single-domain antibody-nanoparticles: promising architectures for increased Staphylococcus aureus detection specificity and sensitivity.
  108. (2008). Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol.
  109. (2008). Successful treatment of Clostridium difficile colitis with intravenous
  110. Targeting virulence: a new paradigm for antimicrobial therapy.
  111. (2009). The development of nanobodies for therapeutic applications.
  112. (2009). The mechanisms and efficacy of probiotics in the prevention of Clostridium difficile-associated diarrhoea. Lancet Infect. Dis.
  113. (2009). The role of immunoglobulin for the treatment of Clostridium difficile infection: a systemic review.
  114. (2008). Thermodynamically stable aggregation-resistant antibody domains through directed evolution.
  115. (2008). Tolevamer, an orally administered, toxin-binding polymer for Clostridium difficile-associated diarrhea.
  116. (2009). Toxin B is essential for virulence of Clostridium difficile.
  117. (2005). Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet
  118. (2009). Treatment of Clostridium difficile-associated disease. Gastroenterology
  119. (1991). Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile
  120. (2010). Treatment with monoclonal antibodies against Clostridium difficile toxins.
  121. Use of intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis.