A Mixture of Functionally Oligoclonal Humanized Monoclonal Antibodies That Neutralize Clostridium difficile TcdA and TcdB with High Levels of<i>In Vitro</i>Potency Shows<i>In Vivo</i>Protection in a Hamster Infection Model

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

doi:10.1128/cvi.00625-12

Cited by 46 publications

(63 citation statements)

References 61 publications

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“…In contrast, both actoxumab and bezlotoxumab are significantly less potent against strains of ribotypes 027, 036, 078 (toxinotypes III, X, and V, respectively), and 198 (unknown toxinotype). Shifts in potency for ribotypes 027 and 078 were reported by two other groups utilizing their own versions of actoxumab and bezlotoxumab (referred to in those studies as CDA1 and CDB1/MDX-1388, respectively) (20,21). In the study by Davies et al, the authors reported that CDA1 was "largely impotent" against TcdA from strains of ribotype 027 (20).…”

Section: Discussionmentioning

confidence: 81%

Broad Coverage of Genetically Diverse Strains of Clostridium difficile by Actoxumab and Bezlotoxumab Predicted by In Vitro Neutralization and Epitope Modeling

Hernandez

Racine

Xiao

et al. 2015

Antimicrob Agents Chemother

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Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics. However, it is not known whether the antibody combination will be effective against a broad range of C. difficile strains. As a first step toward addressing this, we tested the ability of actoxumab and bezlotoxumab to neutralize the activities of toxins from a number of clinically relevant and geographically diverse strains of C. difficile. Neutralization potencies, as measured in a cell growth/survival assay with purified toxins from various C. difficile strains, correlated well with antibody/toxin binding affinities. Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans. We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078. Combined with in vitro neutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic. Infection with the Gram-positive, spore-forming, anaerobic bacterium Clostridium difficile is the leading cause of hospital-acquired infectious diarrhea in the developed world and can have potentially life-threatening effects. In the United States, approximately 14,000 deaths per year are attributed to C. difficile infections (CDIs), with an additional 250,000 patients per year requiring hospitalization or an increased length of hospital stay due to infection. As a result, it is estimated that more than $1 billion per year are spent in excess medical costs for treatment of CDIs in the United States (1, 2).C. difficile is transmitted by spores through the fecal-oral route, often in a hospital or health care facility setting. Treatment with broad-spectrum antibiotics, which suppress the normal gut flora, is the primary risk factor for development of CDIs. In the absence of bacterial competition, C. difficile is able to thrive and to colonize the large intestine, leading to symptoms that can include mild to severe diarrhea, fever, pseudomembranous colitis, and toxic megacolon (2). While primary CDIs are generally successfully treated with the current standard-of-care antibiotics vancomycin, metronidazole, and most recently fidaxomicin, over the past decade there has been an increase in antibiotic-resistant and socalled hypervi...

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Section: Discussionmentioning

confidence: 81%

Broad Coverage of Genetically Diverse Strains of Clostridium difficile by Actoxumab and Bezlotoxumab Predicted by In Vitro Neutralization and Epitope Modeling

Hernandez

Racine

Xiao

et al. 2015

Antimicrob Agents Chemother

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“…To date, these conflicting findings have not been explained or resolved. Nonetheless, both toxins are lethal in animal challenge models, and antibodies against TcdA and TcdB can protect against disease (102). The fact remains that despite extensive study for more than 3 decades, the general roles of TcdA and TcdB in disease and their contributions to the overall virulence of C. difficile are not well understood.…”

Section: Factors Important To C Difficile Virulencementioning

confidence: 98%

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Hunt

Ballard

2013

Microbiol Mol Biol Rev

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SUMMARY Clostridium difficile is a Gram-positive, spore-forming organism which infects and colonizes the large intestine, produces potent toxins, triggers inflammation, and causes significant systemic complications. Treating C. difficile infection (CDI) has always been difficult, because the disease is both caused and resolved by antibiotic treatment. For three and a half decades, C. difficile has presented a treatment challenge to clinicians, and the situation took a turn for the worse about 10 years ago. An increase in epidemic outbreaks related to CDI was first noticed around 2003, and these outbreaks correlated with a sudden increase in the mortality rate of this illness. Further studies discovered that these changes in CDI epidemiology were associated with the rapid emergence of hypervirulent strains of C. difficile , now collectively referred to as NAP1/BI/027 strains. The discovery of new epidemic strains of C. difficile has provided a unique opportunity for retrospective and prospective studies that have sought to understand how these strains have essentially replaced more historical strains as a major cause of CDI. Moreover, detailed studies on the pathogenesis of NAP1/BI/027 strains are leading to new hypotheses on how this emerging strain causes severe disease and is more commonly associated with epidemics. In this review, we provide an overview of CDI, discuss critical mechanisms of C. difficile virulence, and explain how differences in virulence-associated factors between historical and newly emerging strains might explain the hypervirulence exhibited by this pathogen during the past decade.

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“…In animal models, MAbs have been shown to reduce the severity and duration of diarrhea, death rate, and rate of recurrence [214] . Literature concerning the administration of a single MAb against either toxin A or toxin B seems to be conflicting; one early study reports that a MAb against toxin A was sufficient to protect form death, while a MAb against toxin B had no effect [215] .…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Clinical update for the diagnosis and treatment ofClostridium difficileinfection

Oldfield

Johnson

2014

WJGPT

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Clostridium difficile infection (CDI) presents a rapidly evolving challenge in the battle against hospitalacquired infections. Recent advances in CDI diagnosis and management include rapid changes in diagnostic approach with the introduction of newer tests, such as detection of glutamate dehydrogenase in stool and polymerase chain reaction to detect the gene for toxin production, which will soon revolutionize the diagnostic approach to CDI. New medications and multiple medical society guidelines have introduced changing concepts in the definitions of severity of CDI and the choice of therapeutic agents, while rapid expansion of data on the efficacy of fecal microbiota transplantation heralds a revolutionary change in the management of patients suffering multiple relapses of CDI. Through a comprehensive review of current medical literature, this article aims to offer an intensive review of the current state of CDI diagnosis, discuss the strengths and limitations of available laboratory tests, compare both current and future treatments options and offer recommendations for best practice strategies.

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A Mixture of Functionally Oligoclonal Humanized Monoclonal Antibodies That Neutralize Clostridium difficile TcdA and TcdB with High Levels ofIn VitroPotency ShowsIn VivoProtection in a Hamster Infection Model

Cited by 46 publications

References 61 publications

Broad Coverage of Genetically Diverse Strains of Clostridium difficile by Actoxumab and Bezlotoxumab Predicted by In Vitro Neutralization and Epitope Modeling

Broad Coverage of Genetically Diverse Strains of Clostridium difficile by Actoxumab and Bezlotoxumab Predicted by In Vitro Neutralization and Epitope Modeling

Variations in Virulence and Molecular Biology among Emerging Strains of Clostridium difficile

Clinical update for the diagnosis and treatment ofClostridium difficileinfection

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