Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin.
Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin.
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DOI：
10.1038/s41467-017-00448-0
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发表时间：
2017-09-04
影响因子：
16.6
通讯作者：
Lodish HF
中科院分区：
文献类型：
--
作者：
Huang NJ;Pishesha N;Mukherjee J;Zhang S;Deshycka R;Sudaryo V;Dong M;Shoemaker CB;Lodish HF
循环中较短的半衰期限制了单域抗体(VHHs)等治疗药物的应用。我们利用红细胞来延长VHH的循环半衰期。在这里，我们通过表达VHH与血糖素A或Kell的嵌合蛋白，在红细胞表面表达抗肉毒杆菌神经毒素A(BoNT/A)的VHH。红细胞携带嵌合蛋白的小鼠对致死量(LD50)10,000倍的BONT/A表现出抵抗力，将这些红细胞输注到幼小鼠体内可提供长达28天的保护。我们进一步利用改进的CD34+培养系统来设计表达这些嵌合蛋白的人红细胞。输注这些红细胞的小鼠对高致死剂量的BONT/A具有抵抗力。我们证明，表达VHHs的工程红细胞可以在不引发抑制性免疫反应的情况下提供针对细菌毒素的长期预防保护，并说明我们的治疗应用策略具有广泛的可译性。单链抗体(VHH)在血液循环中的半衰期短，限制了其在治疗上的应用。在这里，作者设计了小鼠和人类红细胞来表达针对其表面的肉毒杆菌神经毒素A(BoNT/A)的VHH，并表明将这些细胞注入小鼠体内可以对高剂量的BoNT/A产生持久的保护。
A short half-life in the circulation limits the application of therapeutics such as single-domain antibodies (VHHs). We utilize red blood cells to prolong the circulatory half-life of VHHs. Here we present VHHs against botulinum neurotoxin A (BoNT/A) on the surface of red blood cells by expressing chimeric proteins of VHHs with Glycophorin A or Kell. Mice whose red blood cells carry the chimeric proteins exhibit resistance to 10,000 times the lethal dose (LD50) of BoNT/A, and transfusion of these red blood cells into naive mice affords protection for up to 28 days. We further utilize an improved CD34+ culture system to engineer human red blood cells that express these chimeric proteins. Mice transfused with these red blood cells are resistant to highly lethal doses of BoNT/A. We demonstrate that engineered red blood cells expressing VHHs can provide prolonged prophylactic protection against bacterial toxins without inducing inhibitory immune responses and illustrates the potentially broad translatability of our strategy for therapeutic applications. The therapeutic use of single-chain antibodies (VHHs) is limited by their short half-life in the circulation. Here the authors engineer mouse and human red blood cells to express VHHs against botulinum neurotoxin A (BoNT/A) on their surface and show that an infusion of these cells into mice confers long lasting protection against a high dose of BoNT/A.
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影响因子：
12.4
作者：
Chakravarty R;Goel S;Cai W
通讯作者：
Cai W
影响因子：
20.3
作者：
Griffiths, Rebecca E.;Kupzig, Sabine;Anstee, David J.
通讯作者：
Anstee, David J.
DOI：
10.1073/pnas.1106634108
发表时间：
2011-07-05
影响因子：
11.1
作者：
Hu, Che-Ming J.;Zhang, Li;Zhang, Liangfang
通讯作者：
Zhang, Liangfang
影响因子：
3.7
作者：
Adekar, Sharad P.;Segan, Andrew T.;Dessain, Scott K.
通讯作者：
Dessain, Scott K.
影响因子：
46.9
作者：
Giarratana, MC;Kobari, L;Douay, L
通讯作者：
Douay, L