Targeted Killing of Herpesvirus-Infected Cells

靶向杀死疱疹病毒感染的细胞

• 批准号: 8157057
• 负责人: Edward Berger
• 金额: $ 46.47万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157057
• 关键词: Cells; Herpesviridae; killings

Our initial focus is on MCD, a syndrome in which infected B cells are in the lytic phase of the viral replication cycle. Infected cells express several KSHV structural glycoproteins at the surface, including gH/gL, gB, and K8.1A. Though a relatively rare disease, MCD incidence continues to rise despite antiretroviral therapy and the associated improvements in immune function. MCD if a life-threatening disease (median life expectancy <3 years after diagnosis), and no standards for clinical management have been developed. Hence immunotoxins to selectively kill infected B cells may prove beneficial. We previously reported the design and characterization of two new PE-based immunotoxins targeting gH, developed from murine mAbs isolated in our laboratory. One of these, YC15-PE38, was found to directly kill gH transfectant cell lines with high potency (IC50 150 pM). When tested against Vero-219 cells carrying an episomal recombinant KSHV genome, the immunotoxin potently inhibited virus production (IC50 500 pM); controls verified that this effect was due to selective killing of the virus-producing cells. In combination drug experiments, the immunotoxin and ganciclovir demonstrated complementary inhibitory activities against infectious virus production form Vero-219 cells. In a collaborative effort (B. Chandran), we have produced an immunotoxin against K8.1A that also displays activity against virus production from Vero-219 cells.

我们最初的重点是MCD，MCD是一种综合征，其中感染的B细胞处于病毒复制周期的裂解阶段。感染的细胞在表面表达几种KSHV结构糖蛋白，包括GH/GL，GB和K8.1A。尽管是一种相对罕见的疾病，但尽管抗逆转录病毒疗法以及免疫功能的改善，MCD的发病率仍在继续升高。 MCD如果危及生命的疾病（诊断后3年的预期寿命<3年），并且尚未制定临床管理标准。因此，免疫毒素有选择地杀死感染的B细胞可能有益。我们之前报道了两种新的基于PE的免疫毒素的设计和表征，这些免疫毒素是由我们实验室中分离出的鼠mAB开发的。其中之一，YC15-PE38，直接杀死高效力（IC50 150 pm）的GH转染剂细胞系。当针对带有偶发重组KSHV基因组的VERO-219细胞进行测试时，免疫毒素会有效抑制病毒的产生（IC50 500 PM）；对照验证了这种作用是由于选择性杀死病毒的细胞。在联合药物实验中，免疫毒素和ganciclovir表现出对感染性病毒产生的互补抑制活性，形成了VERO-219细胞。在协作努力（B. Chandran）中，我们对K8.1A产生了一种免疫毒素，该免疫毒素也显示出对Vero-219细胞的病毒产生的活性。