Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Department of Infectious Disease and Global Health, Tufts University, North Grafton, Massachusetts, USA.
Antimicrob Agents Chemother. 2021 Feb 17;65(3). doi: 10.1128/AAC.01469-20.
Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole anthelmintics. However, benzimidazole efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here, we developed an active pharmaceutical ingredient (API) containing Cry5B compatible with MDA. We expressed Cry5B in asporogenous during vegetative phase, forming cytosolic crystals. These cteria with ytosolic rystals (BaCC) were rendered inviable (inactivated BaCC [IBaCC]) with food-grade essential oils. IBaCC potency was validated against nematodes. IBaCC was also potent against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINs in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg body weight Cry5B IBaCC (the curative single dose is 40 mg/kg) was nontoxic to hamsters and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.
人体胃肠道线虫（GINs），例如钩虫，会对儿童的生长、认知、营养、教育程度、收入、生产力和怀孕产生负面影响。数以亿计的人接受捐赠的苯并咪唑驱虫药的大规模药物治疗（MDA）。然而，苯并咪唑类药物对 GINs 的疗效并不理想，疗效降低/不佳的情况时有发生。开发一种用于 MDA 的驱虫药是一项艰巨的任务：它必须安全、有效、廉价、无需冷链且可大规模扩展。晶体蛋白 5B（Cry5B）具有驱虫特性，可以填补这一空白。在这里，我们开发了一种含有 Cry5B 的活性药物成分（API），该成分与 MDA 兼容。我们在营养期表达 Cry5B，形成细胞质晶体。这些含有细胞质晶体的细菌（BaCC）用食品级精油使其失去活力（失活的 BaCC [IBaCC]）。IBaCC 对线虫的效力进行了验证。IBaCC 对仓鼠中的人体钩虫感染也有效。IBaCC 的生产已成功扩大到 350 升在合同制造设施。一种简单的、适合目的的配方可防止胃酸消化，并对粉末状 IBaCC 进行了处理，然后在仓鼠和小鼠中用于防治 GINs。一项初步组织病理学研究和血液化学研究表明，每天连续五次给予 200mg/kg 体重的 Cry5B IBaCC（治愈剂量为 40mg/kg）对仓鼠无毒，完全安全。IBaCC 是一种安全、廉价、高效、易于制造且可扩展的驱虫药，可用于 MDA，代表了治疗人类 GINs 的新范例。
