Antibody Protection against Botulinum Neurotoxin Intoxication in Mice

Cheng, Luisa W.; Stanker, Larry H.; Henderson, Thomas A.; Lou, Jianlong; Marks, James D.

doi:10.1128/iai.00405-09

Cited by 84 publications

(85 citation statements)

References 31 publications

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“…A recent study in which mice were orally intoxicated with botulinum neurotoxin serotype A (BotA) and then treated by passive Ab transfer demonstrated that differences of just 1 to 2 h in antibody administration time points resulted in the loss of the capacity to rescue intoxicated animals (44). We speculate, therefore, that as with BotA, once Stx2a is sequestered in target tissues (the kidneys), passive Ab transfer is not able to rescue intoxicated animals.…”

Section: Discussionmentioning

confidence: 90%

Oral Intoxication of Mice with Shiga Toxin Type 2a (Stx2a) and Protection by Anti-Stx2a Monoclonal Antibody 11E10

et al. 2014

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Shiga toxin (Stx)-producing Escherichia coli (STEC) strains cause food-borne outbreaks of hemorrhagic colitis and, less commonly, a serious kidney-damaging sequela called the hemolytic uremic syndrome (HUS). Stx, the primary virulence factor expressed by STEC, is an AB 5 toxin with two antigenically distinct forms, Stx1a and Stx2a. Although both toxins have similar biological activities, Stx2a is more frequently produced by STEC strains that cause HUS than is Stx1a. Here we asked whether Stx1a and Stx2a act differently when delivered orally by gavage. We found that Stx2a had a 50% lethal dose (LD 50 ) of 2.9 g, but no morbidity occurred after oral intoxication with up to 157 g of Stx1a. We also compared several biochemical and histological parameters in mice intoxicated orally versus intraperitoneally with Stx2a. We discovered that both intoxication routes caused similar increases in serum creatinine and blood urea nitrogen, indicative of kidney damage, as well as electrolyte imbalances and weight loss in the animals. Furthermore, kidney sections from Stx2a-intoxicated mice revealed multifocal, acute tubular necrosis (ATN). Of particular note, we detected Stx2a in kidney sections from orally intoxicated mice in the same region as the epithelial cell type in which ATN was detected. Lastly, we showed reduced renal damage, as determined by renal biomarkers and histopathology, and full protection of orally intoxicated mice with monoclonal antibody (MAb) 11E10 directed against the toxin A subunit; conversely, an irrelevant MAb had no therapeutic effect. Orally intoxicated mice could be rescued by MAb 11E10 6 h but not 24 h after Stx2a delivery.

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Section: Discussionmentioning

confidence: 90%

Oral Intoxication of Mice with Shiga Toxin Type 2a (Stx2a) and Protection by Anti-Stx2a Monoclonal Antibody 11E10

et al. 2014

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“…While cooperativity and synergism of monoclonal antibody mixtures have been reported in the past (16)(17)(18)(19), emerging data have illustrated striking examples of situations wherein the activity of a monoclonal antibody can be drastically altered when assessed in the context of other antibodies (20,21). Indeed, the benefits of using polyclonal antibody preparations to treat disease in therapeutic settings are just beginning to be realized (22).…”

mentioning

confidence: 99%

Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Mullarkey

Duty

et al. 2015

J Virol

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Current influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of "universal" influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferior in vitro but was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during "universal" influenza virus vaccine design. IMPORTANCEInfluenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a "universal" influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of "universal" influenza virus vaccines and therapeutics. I nfluenza A viruses (IAVs) remain one of the most pressing global public health concerns due to their widespread distribution, rapid evolution, and potential for reassortment (1). These traits contribute to the abil...

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“…High valency of binding may be important in multiple respects for Tcd neutralization. First, antigens decorated with multiple antibody Fc domains are cleared faster and more effectively from circulation than those bearing one MAb/Fc (72,73), and such clearance can contribute significantly to neutralization potential in vivo (65). Since circulating toxin has been suspected in patients (74,75) and has been demonstrated in a piglet model of infection (76), improved toxin clearance may offer clinical advantage to some patients.…”

Section: 88mentioning

confidence: 99%