FDA approves antitoxin antibody

Mullard, Asher

doi:10.1038/nrd.2016.257

Cited by 13 publications

(13 citation statements)

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“…New nano-preparation targeting bacterial components responsible for virulence effect of bacteria, such as toxins, may be a promising challenge in the area of antibacterial medications. Bezlotoxumab was the first antitoxin, approved in 2016, as a human monoclonal antibody targeting toxin B of Clostridium difficile [214]. A certain number of anti-toxin agents such as monoclonal antibodies targeting S. aureus' α-toxin are in the clinical development, in addition to monoclonal antibodies that target type III toxins secretion moiety of P. aeruginosa [215].…”

Section: Anti-toxin Agentsmentioning

confidence: 99%

Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations

et al. 2020

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Based on the recent reports of World Health Organization, increased antibiotic resistance prevalence among bacteria represents the greatest challenge to human health. In addition, the poor solubility, stability, and side effects that lead to inefficiency of the current antibacterial therapy prompted the researchers to explore new innovative strategies to overcome such resilient microbes. Hence, novel antibiotic delivery systems are in high demand. Nanotechnology has attracted considerable interest due to their favored physicochemical properties, drug targeting efficiency, enhanced uptake, and biodistribution. The present review focuses on the recent applications of organic (liposomes, lipid-based nanoparticles, polymeric micelles, and polymeric nanoparticles), and inorganic (silver, silica, magnetic, zinc oxide (ZnO), cobalt, selenium, and cadmium) nanosystems in the domain of antibacterial delivery. We provide a concise description of the characteristics of each system that render it suitable as an antibacterial delivery agent. We also highlight the recent promising innovations used to overcome antibacterial resistance, including the use of lipid polymer nanoparticles, nonlamellar liquid crystalline nanoparticles, anti-microbial oligonucleotides, smart responsive materials, cationic peptides, and natural compounds. We further discuss the applications of antimicrobial photodynamic therapy, combination drug therapy, nano antibiotic strategy, and phage therapy, and their impact on evading antibacterial resistance. Finally, we report on the formulations that made their way towards clinical application.

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Section: Anti-toxin Agentsmentioning

confidence: 99%

Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations

et al. 2020

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“… 26 Bezlotoxumab is approved for use only in the adult (≥18 years of age) population while on concomitant anti-CDI therapy and has no established role as monotherapy agent or in treatment of CDI. 28 The precise timing of infusion of bezlotoxumab in correlation to the standard-of-care CDI therapy is undefined. In the Phase III trials, bezlotoxumab was generally administered an average of 3 days from the standard-of-care treatment.…”

Section: Pharmacokinetics (Pk) and Pharmacodynamics (Pd)mentioning

confidence: 99%

“…Based on Phase III clinical trial results, the US Food and Drug administration (FDA) approved the use of bezlotoxumab in prevention of recurrent CDI in October 2016. 28 Bezlotoxumab is indicated for use in adult patients (≥18 years of age) at high risk of recurrence, undergoing the standard-of-care antimicrobial treatment for CDI. Patients with CDI in the previous 6 months, severe CDI, aged ≥65 years, ongoing antibacterial therapy, immunocompromising conditions and CDI due to hypervirulent ribotype strains 027, 078 or 244 were defined to be at high risk for recurrence.…”

Section: Efficacy Studiesmentioning

confidence: 99%

Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent <em>Clostridium difficile </em>infection

Navalkele¹,

Chopra²

2018

BTT

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Clostridium difficile infection (CDI) is the most common health care-acquired infection associated with high hospital expenditures. The incidence of subsequent recurrent CDI increases with prior episodes of CDI, 15%–35% risk after primary CDI to 35%–65% risk after the first recurrent episode. Recurrent CDI is one of the most challenging and a very difficult to treat infections. Standard guidelines provide recommendations on treatment of primary CDI. However, treatment choices for recurrent CDI are limited. Recent research studies have focused on the discovery of newer alternatives for prevention of recurrent CDI targeting prime virulence factors involved in C. difficile pathogenesis. Bezlotoxumab is a human monoclonal antibody directed against C. difficile toxin B. Multiple in vitro and in vivo animal studies have demonstrated direct binding of bezlotoxumab to C. difficile toxin B preventing intestinal epithelial damage and colitis. Furthermore, this monoclonal antibody mediates early reconstitution of gut microbiota preventing risk of recurrent CDI. Randomized placebo-controlled trials showed concomitant administration of a single intravenous dose of 10 mg/kg of bezlotoxumab, in patients on standard-of-care therapy for CDI, had no substantial effect on clinical cure rates but significantly reduced the incidence of recurrent CDI (~40%). It shows efficacy against multiple strains, including the epidemic BI/NAP1/027 strain. Bezlotoxumab is a US Food and Drug administration-approved, safe and well-tolerated drug with low risk of serious adverse events and drug–drug interactions. Bezlotoxumab has emerged as a novel dynamic adjunctive therapy for prevention of recurrent CDI. Further studies on real-world experience with bezlotoxumab and its impact in reducing rates of recurrent CDI are needed.

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“…Both of the mAbs bind the C-terminal CROPs domain of their respective toxins and neutralize toxicity in cell culture by blocking cell-surface binding (21,22). Treatment with bezlotoxumab alone has been shown to reduce recurrence of CDI in Phase III clinical trials (23) and has been approved by the United States Food and Drug Administration (24), validating the use of anti-TcdB antibodies as supportive therapy.…”

Section: Clostridium Difficile Infection Is the Leading Cause Of Hospmentioning

confidence: 99%

A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

Kroh

Chandrasekaran

Zhang

et al. 2018

Journal of Biological Chemistry

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infection is the leading cause of hospital-acquired diarrhea and is mediated by the actions of two toxins, TcdA and TcdB. The toxins perturb host cell function through a multistep process of receptor binding, endocytosis, low pH-induced pore formation, and the translocation and delivery of an N-terminal glucosyltransferase domain that inactivates host GTPases. Infection studies with isogenic strains having defined toxin deletions have established TcdB as an important target for therapeutic development. Monoclonal antibodies that neutralize TcdB function have been shown to protect against infection in animal models and reduce recurrence in humans. Here, we report the mechanism of TcdB neutralization by PA41, a humanized monoclonal antibody capable of neutralizing TcdB from a diverse array of strains. Through a combination of structural, biochemical, and cell functional studies, involving X-ray crystallography and EM, we show that PA41 recognizes a single, highly conserved epitope on the TcdB glucosyltransferase domain and blocks productive translocation and delivery of the enzymatic cargo into the host cell. Our study reveals a unique mechanism of toxin neutralization by a monoclonal antibody, which involves targeting a process that is conserved across the large clostridial glucosylating toxins. The PA41 antibody described here provides a valuable tool for dissecting the mechanism of toxin pore formation and translocation across the endosomal membrane.

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FDA approves antitoxin antibody

Cited by 13 publications

References 0 publications

Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations

Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations

Bezlotoxumab: an emerging monoclonal antibody therapy for prevention of recurrent <em>Clostridium difficile </em>infection

A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

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