Efficacy of Prophylactic and Therapeutic Administration of Antitoxin for Inhalation Botulism

Franz, David R.; Pitt, M. Louise M.; Clayton, M A; Hanes, Martha A.; Rose, Kenneth J.

doi:10.1007/978-1-4757-9542-4_52

Cited by 54 publications

(51 citation statements)

References 3 publications

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“…Postexposure vaccination is useless, due to the rapid onset of disease. Toxin-neutralizing antibody (Ab) can be used for pre-or postexposure prophylaxis or for treatment (14). Small quantities of both equine antitoxin and human botulinum immunoglobulin (Ig) exist and are currently used to treat adult (7,19) and infant (4) botulism, respectively.…”

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confidence: 99%

Sequence Variation within Botulinum Neurotoxin Serotypes Impacts Antibody Binding and Neutralization

et al. 2005

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The botulinum neurotoxins (BoNTs) are category A biothreat agents which have been the focus of intensive efforts to develop vaccines and antibody-based prophylaxis and treatment. Such approaches must take into account the extensive BoNT sequence variability; the seven BoNT serotypes differ by up to 70% at the amino acid level. Here, we have analyzed 49 complete published sequences of BoNTs and show that all toxins also exhibit variability within serotypes ranging between 2.6 and 31.6%. To determine the impact of such sequence differences on immune recognition, we studied the binding and neutralization capacity of six BoNT serotype A (BoNT/A) monoclonal antibodies (MAbs) to BoNT/A1 and BoNT/A2, which differ by 10% at the amino acid level. While all six MAbs bound BoNT/A1 with high affinity, three of the six MAbs showed a marked reduction in binding affinity of 500-to more than 1,000-fold to BoNT/A2 toxin. Binding results predicted in vivo toxin neutralization; MAbs or MAb combinations that potently neutralized A1 toxin but did not bind A2 toxin had minimal neutralizing capacity for A2 toxin. This was most striking for a combination of three binding domain MAbs which together neutralized >40,000 mouse 50% lethal doses (LD 50 s) of A1 toxin but less than 500 LD 50 s of A2 toxin. Combining three MAbs which bound both A1 and A2 toxins potently neutralized both toxins. We conclude that sequence variability exists within all toxin serotypes, and this impacts monoclonal antibody binding and neutralization. Such subtype sequence variability must be accounted for when generating and evaluating diagnostic and therapeutic antibodies.

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confidence: 99%

Sequence Variation within Botulinum Neurotoxin Serotypes Impacts Antibody Binding and Neutralization

et al. 2005

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“…Postexposure vaccination is useless because of the rapid onset of disease. Toxin neutralizing antibody (Ab) can be used for pre-or postexposure prophylaxis or for treatment (16). Small quantities of both equine antitoxin and human botulinum immune globulin exist and are currently used to treat adult (17,18) and infant botulism (19), respectively.…”

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confidence: 99%

“…In this work, we report that BoNT serotype A (BoNT͞A) can be very potently neutralized in vitro and in vivo by combining two or three mAbs, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents. (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) g͞ml in 10 mM acetate, pH 3.5-4.5) was coupled to a CM5 sensor chip by using N-hydroxysuccinimide-N-ethyl-NЈ-(dimethylaminopropyl)-carbodiimide chemistry. The association rate constant for purified BoNT͞A H C was measured under continuous flow of 15 l͞min, using a concentration range of 50-800 nM.…”

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confidence: 99%

Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody

Nowakowski

Wang

Powers

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

303

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The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT͞A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT͞A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents. monoclonal antibody ͉ immunotherapy ͉ antibody engineering ͉ vaccine ͉ phage display

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“…44,62 In contrast, the clinical syndrome of descending flaccid paralysis owing to botulinum neurotoxins is essentially the same whether the toxin is administered by way of gastrointestinal or aerosol exposure. 19,52 Therefore, the pathogenic mechanisms of BSATinduced diseases are complicated and involve a number of host and pathogen factors, as we discuss throughout this review.…”

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confidence: 99%

Aerobiology and Inhalation Exposure to Biological Select Agents and Toxins

2010

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Aerosol is the most likely route of dissemination of biological select agents and toxins in a bioterrorist attack, regardless of the natural route of exposure to the agent. The use of animal models for testing preventative and therapeutic countermeasures requires knowledge of the pathogenesis of disease after inhalation exposure. Factors that relate to outcome after respiratory exposure include the inherent infectivity and virulence and/or toxicity of the agent in the host under investigation, in addition to characteristics of the aerosol particle and host that affect the delivered dose of, and host response to, the inhaled material. This introductory article discusses the emerging science of aerobiology and the unique features of respiratory tract anatomy, physiology, and immunology that are relevant to the pathogenesis of aerosolized biothreat agents.

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Efficacy of Prophylactic and Therapeutic Administration of Antitoxin for Inhalation Botulism

Cited by 54 publications

References 3 publications

Sequence Variation within Botulinum Neurotoxin Serotypes Impacts Antibody Binding and Neutralization

Sequence Variation within Botulinum Neurotoxin Serotypes Impacts Antibody Binding and Neutralization

Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody

Aerobiology and Inhalation Exposure to Biological Select Agents and Toxins

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