Fully human MAP-fusion protein selectively targets and eliminates proliferating CD64+ M1 macrophages
Fully human MAP-fusion protein selectively targets and eliminates proliferating CD64+ M1 macrophages
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DOI：
10.1038/icb.2016.4
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发表时间：
2016-05-01
影响因子：
4
通讯作者：
Thepen, Theo
中科院分区：
文献类型：
--
作者：
Hristodorov, Dmitrij;Mladenov, Radoslav;Thepen, Theo
经典的免疫毒素包括结合组分（例如，配体、抗体或其片段）和通常来源于细菌或植物的细胞毒性组分（例如，假单胞菌外毒素A或蓖麻毒素）。尽管体外试验成功，但免疫毒素的临床开发受到免疫原性和不令人满意的安全性的阻碍。因此，研究集中在适合于开发溶细胞融合蛋白（CFP）的全人促凋亡组分上。我们最近报道，人微管相关蛋白tau（MAP）可以诱导细胞凋亡时，交付到快速增殖的癌细胞。在这里，我们描述了一种新的全人CFP，称为H22（scFv）-MAP，它特异性靶向CD 64（+）细胞。我们表明H22（scFv）-MAP可以在体外有效杀死增殖的HL-60前单核细胞。此外，在皮肤慢性炎症的转基因小鼠模型中，人CFP特异性消除极化的M1巨噬细胞。由于M1巨噬细胞促进许多慢性炎症性疾病的发病机制，因此用H22（scFv）-MAP靶向该细胞群可能有助于治疗特应性皮炎、类风湿性关节炎和炎症性肠病等疾病。
Classical immunotoxins compromise a binding component (for example, a ligand, antibody or fragment thereof) and a cytotoxic component, usually derived from bacteria or plants (for example, Pseudomonas exotoxin A or ricin). Despite successful testing in vitro, the clinical development of immunotoxins has been hampered by immunogenicity and unsatisfactory safety profiles. Therefore, research has focused on fully human pro-apoptotic components suitable for the development of cytolytic fusion proteins (CFP). We recently reported that human microtubule-associated protein tau (MAP) can induce apoptosis when delivered to rapidly proliferating cancer cells. Here, we describe a new fully human CFP called H22(scFv)-MAP, which specifically targets CD64(+) cells. We show that H22(scFv)-MAP can efficiently kill proliferating HL-60 pro-monocytic cells in vitro. In addition, the human CFP specifically eliminates polarized M1 macrophages in a transgenic mouse model of cutaneous chronic inflammation. Because M1 macrophages promote the pathogenesis of many chronic inflammatory diseases, targeting this cell population with H22(scFv)-MAP could help to treat diseases such as atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease.