Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed

Sawada-Hirai, Ritsuko; Jiang, Ivy; Wang, Fei; Sun, Shu Man; Nedellec, Rebecca; Ruther, Paul; Álvarez, Ana; Millis, Diane; Morrow, Phillip R.; Kang, Angray S.

doi:10.1186/1476-8518-2-5

Cited by 86 publications

(17 citation statements)

References 27 publications

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“…Hence, anthrax presents a very good model for antidote design, and antitoxins that act upon the mechanism of action of the toxin (including toxin binding, assembly, translocation into target cells) have been developed 12,[24][25][26][27] . This suggests that intrinsic neutralizing epitopes exist within the toxin structural motif.…”

Section: Introductionmentioning

confidence: 99%

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Zhou

Carney

Janda

2008

Bioorganic & Medicinal Chemistry

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A less than adequate therapeutic plan for the treatment of anthrax in the 2001 bioterrorism attacks has highlighted the importance of developing alternative or complementary therapeutic approaches for biothreat agents. In these regards passive immunization possesses several important advantages over active vaccination and the use of antibiotics, as it can provide immediate protection against Bacillus anthracis. Herein, we report the selection and characterization of several human monoclonal neutralizing antibodies against the toxin of B. anthracis from a phage displayed human scFv library. In total fifteen clones were selected with distinct sequences and high specificity to protective antigen and thus were the subject of a series of both biophysical and cell-based cytotoxicity assays. From this panel of antibodies a set of neutralizing antibodies were identified, of which clone A8 recognizes the lethal (and/or edema) factor binding domain, and clone F1, G11 and G12 recognize the cellular receptor binding domain within protective antigen. It was noted that all clones distinguish a conformational epitope existing on the protective antigen; this steric relationship was uncovered using a sequential epitope mapping approach. For each neutralizing antibody, the kinetic constants were determined by surface plasmon resonance, while the potency of protection was established using a two-tier macrophage cytotoxicity assay. Among the neutralizing antibodies identified, clone F1 possessed the highest affinity to protective antigen, and provided superior protection from lethal toxin in the cell cytotoxicity assay. The data presented provides to the ever-growing arsenal of immunological and functional analysis of monoclonal antibodies to the exotoxins of anthrax. In addition it grants new candidates for the prophylaxis and therapeutic treatment against this toxin.

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Section: Introductionmentioning

confidence: 99%

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Zhou

Carney

Janda

2008

Bioorganic & Medicinal Chemistry

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“…Monoclonal antibodies with high affinity for PA 83 were developed from lymphocytes of an individual vaccinated with AVA and hybridoma technology and two, AVP-21D9 and AVP-22G12, were protective in LT-challenged macrophages and Fisher rats [72]. The inhibitory effects of the mAbs were related primarily to interference with PA 63 heptamer formation and not PA 83 binding to host receptors or toxic moiety binding to the oligomer complex [73].…”

Section: Toxin-directed Therapies For the Management Of B Anthracmentioning

confidence: 99%

An overview of investigational toxin-directed therapies for the adjunctive management ofBacillus anthracisinfection and sepsis

Ohanjanian

Remy

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction Sepsis with Bacillus anthracis infection has a very high mortality rate despite appropriate antibiotic and supportive therapies. Over the past 15 years, recent outbreaks in the US and in Europe, coupled with anthrax's bioterrorism weapon potential, have stimulated efforts to develop adjunctive therapies to improve clinical outcomes. Since lethal toxin and edema toxin (LT and ET) make central contributions to the pathogenesis of B. anthracis, these have been major targets in this effort. Areas covered Here, the authors review different investigative biopharmaceuticals that have been recently identified for their therapeutic potential as inhibitors of LT or ET. Among these inhibitors are two antibody preparations that have been included in the Strategic National Stockpile (SNS) and several more that have reached Phase I testing. Presently, however, many of these candidate agents have only been studied in vitro and very few tested in bacteria-challenged models. Expert opinion Although a large number of drugs have been identified as potential therapeutic inhibitors of LT and ET, in most cases their testing has been limited. The use of the two SNS antibody therapies during a large-scale exposure to B. anthracis will be difficult. Further testing and development of agents with oral bioavailability and relatively long shelf lives should be a focus for future research.

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“…A variety of approaches have been taken to intervene at different points of this process to prevent anthrax toxin function. Human antibodies against PA that block receptor binding 18 and antibodies specific for lethal factor (LF) that interfere with assembly of the toxin components 19 have been shown to prevent lethal toxin induced death in rodents. Soluble TEM8/ATR and CMG2 proteins have also been shown to be effective in cell culture, preventing anthrax toxin receptor binding.…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors of anthrax lethal factor toxin

Williams

Khan

Cardinale

et al. 2014

Bioorganic & Medicinal Chemistry

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Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed

Cited by 86 publications

References 27 publications

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin

An overview of investigational toxin-directed therapies for the adjunctive management ofBacillus anthracisinfection and sepsis

Small molecule inhibitors of anthrax lethal factor toxin

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