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Enhanced neutralization potency of botulinum neurotoxin antibodies using a red blood cell-targeting fusion protein.

机译：Enhanced neutralization potency of botulinum neurotoxin antibodies using a red blood cell-targeting fusion protein.

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Botulinum neurotoxin (BoNT) potently inhibits cholinergic signaling at the neuromuscular junction. The ideal countermeasures for BoNT exposure are monoclonal antibodies or BoNT antisera, which form BoNT-containing immune complexes that are rapidly cleared from the general circulation. Clearance of opsonized toxins may involve complement receptor-mediated immunoadherence to red blood cells (RBC) in primates or to platelets in rodents. Methods of enhancing immunoadherence of BoNT-specific antibodies may increase their potency in vivo. We designed a novel fusion protein (FP) to link biotinylated molecules to glycophorin A (GPA) on the RBC surface. The FP consists of an scFv specific for murine GPA fused to streptavidin. FP:mAb:BoNT complexes bound specifically to the RBC surface in vitro. In a mouse model of BoNT neutralization, the FP increased the potency of single and double antibody combinations in BoNT neutralization. A combination of two antibodies with the FP gave complete neutralization of 5,000 LD50 BoNT in mice. Neutralization in vivo was dependent on biotinylation of both antibodies and correlated with a reduction of plasma BoNT levels. In a post-exposure model of intoxication, FP:mAb complexes gave complete protection from a lethal BoNT/A1 dose when administered within 2 hours of toxin exposure. In a pre-exposure prophylaxis model, mice were fully protected for 72 hours following administration of the FP:mAb complex. These results demonstrate that RBC-targeted immunoadherence through the FP is a potent enhancer of BoNT neutralization by antibodies in vivo.
机译：肉毒杆菌神经毒素（BoNT）有效抑制神经肌肉接头处的胆碱能信号传导。 BoNT暴露的理想对策是单克隆抗体或BoNT抗血清，它们形成含BoNT的免疫复合物，这些复合物可从一般循环中迅速清除。调理毒素的清除可能涉及补体受体介导的对灵长类动物的红细胞（RBC）或啮齿类动物的血小板的免疫粘附。增强BoNT特异性抗体免疫粘附力的方法可能会提高其体内效力。我们设计了一种新型融合蛋白（FP），将生物素化的分子与RBC表面的糖蛋白A（GPA）连接起来。 FP由融合至链霉亲和素的鼠GPA的特异性scFv组成。 FP：mAb：BoNT复合物在体外特异性结合到RBC表面。在BoNT中和的小鼠模型中，FP增加了BoNT中和中单抗体和双抗体组合的效力。两种抗体与FP的组合可在小鼠中完全中和5,000 LD50 BoNT。体内中和取决于两种抗体的生物素化，并与血浆BoNT水平降低相关。在中毒的暴露后模型中，当在毒素暴露后2小时内施用FP：mAb复合物可完全抵抗致命的BoNT / A1剂量。在暴露前预防模型中，在施用FP：mAb复合物后，小鼠受到完全保护72小时。这些结果表明，通过FP的RBC靶向免疫粘附是体内抗体对BoNT中和的有效增强剂。

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