文章：

基于颗粒酶B的抗CD30细胞溶解融合蛋白在小鼠模型中对PI-9阳性经典霍奇金淋巴瘤细胞的作用

Efficacy of an adapted granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model

原文发布日期：2013-03-22

DOI: 10.1038/bcj.2013.4

类型: Original Article

开放获取: 是

英文摘要：

Tumors develop when infiltrating immune cells contribute growth stimuli, and cancer cells are selected to survive within such a cytotoxic microenvironment. One possible immune-escape mechanism is the upregulation of PI-9 (Serpin B9) within cancer cells. This serine proteinase inhibitor selectively inactivates apoptosis-inducing granzyme B (GrB) from cytotoxic granules of innate immune cells. We demonstrate that most classical Hodgkin lymphoma (cHL)-derived cell lines express PI-9, which protects them against the GrB attack and thereby renders them resistant against GrB-based immunotherapeutics. To circumvent this disadvantage, we developed PI-9-insensitive human GrB mutants as fusion proteins to target the Hodgkin-selective receptor CD30. In contrast to the wild-type GrB, a R201K point-mutated GrB construct most efficiently killed PI-9-positive and -negative cHL cells. This was tested in vitro and also in vivo whereby a novel optical imaging-based tumor model with HL cell line L428 was applied. Therefore, this variant, as part of the next generation immunotherapeutics, also named cytolytic fusion proteins showing reduced immunogenicity, is a promising molecule for (targeted) therapy of patients with relapsing malignancies, such as cHL, and possibly other PI-9-positive malignancies, such as breast or lung carcinoma.

摘要翻译： 

当浸润的免疫细胞参与生长刺激时，肿瘤便会发展，而癌细胞则被选择在这种细胞毒性微环境中存活。一种可能的免疫逃逸机制是癌细胞中PI-9（Serpin B9）的上调。这种丝氨酸蛋白酶抑制剂选择性地灭活来自天然免疫细胞毒性颗粒的凋亡诱导颗粒酶B（GrB）。我们证明，大多数经典霍奇金淋巴瘤（cHL）来源的细胞系表达PI-9，这保护它们免受GrB攻击，从而使它们对基于GrB的免疫疗法产生抵抗。为了克服这一缺点，我们开发了不敏感于PI-9的人GrB突变体作为融合蛋白，以靶向霍奇金选择性受体CD30。与野生型GrB相比，R201K点突变的GrB构建体最高效地杀死了PI-9阳性和阴性的cHL细胞。这一点在体外和体内均进行了测试，其中应用了基于光学成像的新型肿瘤模型与HL细胞系L428。因此，这种变体作为下一代免疫疗法的一部分，也被称为显示降低免疫原性的溶细胞融合蛋白，是（靶向）治疗复发恶性肿瘤（如cHL）以及其他可能的PI-9阳性恶性肿瘤（如乳腺癌或肺癌）患者的有前景的分子。

原文链接：

Efficacy of an adapted granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model