Antibody Against TcdB, but Not TcdA, Prevents Development of Gastrointestinal and Systemic Clostridium difficile Disease

Steele, Jennifer; Mukherjee, Jean; Parry, N.; Tzipori, Saul

doi:10.1093/infdis/jis669

Cited by 99 publications

(101 citation statements)

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“…10-12 Neutralization of both toxins appears to be necessary for maximal protection in rodents, but neutralization of toxin B alone appears to be sufficient in piglets. 13 In humans, the level of circulating antibodies against toxin A 14,15 or toxin B 16 has been correlated with protection against primary and recurrent C. difficile infection.A new approach to the prevention of recurrent C. difficile infection is the administration of monoclonal antibodies against C. difficile toxins (in addition to antibiotic therapy) as a form of passive immunity. Actoxumab (MK-3415/GS-CDA1/ CDA1) and bezlotoxumab (MK-6072/MDX-1388/ CDB1) are fully human monoclonal antibodies that bind and neutralize C. difficile toxins A and B, respectively.…”

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confidence: 99%

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Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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BACKGROUNDClostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODSWe conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTSIn both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.: CONCLUSIONSAmong participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. 306T h e ne w e ngl a nd jou r na l o f m e dicine I n high-income countries, Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. 1,2 After completing initial antibiotic therapy, up to 35% of patients have recurrent C. difficile infection, 3,4 which is more difficult to treat and is associated with more hospitalizations, more severe outcomes, and higher costs than the first infection and a 50 to 60% chance of repeat recurrent infections. 5,6 Currently, no therapy has been approved to prevent recurrent C. difficile infection.Passive or active immunization against C. difficile toxins A and B is protective in animals that are challenged with toxigenic C. difficile, 7-9 which underscores the key importance of the toxins in causing the symptoms of C. difficile infection. The relative biologic importance of toxins A and B in C. difficile infection is controversial, but it may be host species-dependent. 10-12 Neutralization of both toxins appears to be necessary for maximal protection in rodents, but neutralization of toxin...

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confidence: 99%

“…[10][11][12] Neutralization of both toxins appears to be necessary for maximal protection in rodents, but neutralization of toxin B alone appears to be sufficient in piglets. 13 In humans, the level of circulating antibodies against toxin A 14,15 or toxin B 16 has been correlated with protection against primary and recurrent C. difficile infection.…”

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Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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“…[1][2][3][4][5] We recently published a paper of our experimental results with human monoclonal antibodies used to investigate roles of TcdA and TcdB in the pathogenesis of CDI. 6 Interestingly, we found that only anti-TcdB was required in the piglet model to protect piglets from systemic and gastrointestinal lesions following oral inoculation with C. difficile, and that piglets treated with only anti-TcdA actually fared worse than untreated controls. This finding drew into question the long-standing hypothesis that TcdA was actually more important in the pathogenesis of disease, but was in agreement with other recent work highlighting the importance of TcdB.…”

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confidence: 80%

“…6 Systemic administration of purified toxins allowed us to isolate each toxin from the other and revealed that both are quite potent and elicit severe systemic and gastrointestinal lesions, with each causing differential lesions. In contrast to the in vitro knowledge that TcdB is generally toxic to cells in much lower concentrations, we found the reality in vivo to be the opposite, with rTcdA causing equally severe disease at least a 50-fold lower dose where 2 μg of rTcdA was as toxic as 100 μg of rTcdB.…”

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confidence: 99%

The roles of toxin A and toxin B inClostridium difficileinfection

2013

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“…8,9 In humans, this supplementary infusion to primary antibiotics has shown remarkably lower recurrence rates. 10 Given these encouraging findings, a study was designed to clarify how these targeted serum antibodies access the colonic lumen.…”

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Clostridium difficile infection

2014

The Journal of the American Dental Association

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Clostridium difficile infection (CDI) affects a broad population and has become so widespread the Centers for Disease Control and Prevention rated C. difficile as an urgent threat in 2013. 1,2 Recent basic-science research has focused on understanding the pathogenesis of the disease and alterations in the microbiome causing susceptibility. This manuscript will address two studies likely to influence future understanding and management.Symptomatic CDI results from the bacterial production of two main toxins, toxin A and toxin b (tcdA/B). By increasing colonic mucosal permeability via disruption of cell signaling and their tight junctions, these toxins cause cytoskeletal degradation and death. 3,4 One therapeutic target for CDI is neutralization of tcdA/B, however, treatment with broad intravenous immunoglobulin has had disappointing results. 5 Successive studies showed that patients who are able to elevate their serum immunoglobulin to tcdA are 48 times less likely to have symptomatic initial CDI and following CDI less likely to get recurrent disease. 6,7 Serum immunoglobulins targeting the tcdA/B have become a target for vaccinations and treatment.Human monoclonal antibodies (HMabs) to C. difficile tcdA/B have shown promising results in the treatment of CDI in hamster and piglet models. 8,9 In humans, this supplementary infusion to primary antibiotics has shown remarkably lower recurrence rates. 10 Given these encouraging findings, a study was designed to clarify how these targeted serum antibodies access the colonic lumen. 11 In total, 23 gnotobiotic piglets were randomized into three groups. Twelve received a pathogenic CDI, nine a non-pathogenic strain and two no C. difficile; HMab to tcdA/B were given to each piglet. The piglets were then euthanized 2-4 days after antibody infusion and samples taken of the serum, gastrointestinal contents, and the gastrointestinal tissue. Using enzyme linked immunosorbent assay, concentrations of the infused antibodies in each location were measured and compared. All animals had a similar distribution and concentration within the mucosa of the small and large bowel. HMab was only in significantly elevated concentrations within the colonic lumen of those with pathogenic CDI. 11 When comparing the active study subjects with four historical controls receiving pathogenic CDI with HMab that was irrelevant, those given HMab targeting tcdA/B had less severe disease (defined by ratings of histopathology and symptom score) and lower mortality despite similar colonic concentrations of pathogenic bacteria. 11 The mechanism of translocation remains unclear but a priori hypotheses included either direct leakage across the colonic lumen or active transport through neonatal Fc receptors (FcRn). FcRn are selectively expressed during various infections and have a significant role regulating IgG transport into the colonic lumen. 12 In CDI, FcRn are expressed in both pathogenic and non-pathogenic disease. As HMab was found luminally only in those with pathogenic CDI, transmucosal passage via F...

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Antibody Against TcdB, but Not TcdA, Prevents Development of Gastrointestinal and Systemic Clostridium difficile Disease

Abstract: These results highlight the importance of TcdB in the pathogenesis of CDI and the effectiveness of TcdB-specific antibody in treating CDI. However, the results raise new questions regarding the nature of TcdA interaction with therapeutic antibodies.

Cited by 99 publications

References 24 publications

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

The roles of toxin A and toxin B inClostridium difficileinfection

Clostridium difficile infection

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