Evgin Laura, Ilkow Carolina S, Bourgeois-Daigneault Marie-Claude, de Souza Christiano Tanese, Stubbert Lawton, Huh Michael S, Jennings Victoria A, Marguerie Monique, Acuna Sergio A, Keller Brian A, Lefebvre Charles, Falls Theresa, Le Boeuf Fabrice, Auer Rebecca A, Lambris John D, McCart J Andrea, Stojdl David F, Bell John C
Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute , Ottawa, Ontario, Canada.
Mol Ther Oncolytics. 2016 Nov 16;3:16027. doi: 10.1038/mto.2016.27. eCollection 2016.
The systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. While pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. For the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway. We show that this phenotype can be capitalized upon to deliver maraba virus pseudotyped with the lymphocytic choriomeningitis virus glycoprotein in a Fischer rat model in the face of neutralizing antibody through the use of complement modulators. This finding changes the understanding of the humoral immune response to arenaviruses, and also describes methodology to deliver viral vectors to their therapeutic sites of action without the interference of neutralizing antibody.
治疗性病毒（如溶瘤病毒或疫苗）的全身递送受到中和抗体产生的限制。虽然此前用淋巴细胞性脉络丛脑膜炎病毒糖蛋白对弹状病毒进行假型化已允许在小鼠中进行多轮递送，但该策略尚未转化到其他动物模型。我们首次提供了实验证据，表明针对淋巴细胞性脉络丛脑膜炎病毒糖蛋白产生的抗体通过经典途径的激活介导强大的补体依赖性病毒中和作用。我们表明，面对中和抗体时，通过使用补体调节剂，这种表型可被利用来在费希尔大鼠模型中递送用淋巴细胞性脉络丛脑膜炎病毒糖蛋白假型化的马拉巴病毒。这一发现改变了对沙粒病毒体液免疫反应的理解，还描述了在无中和抗体干扰的情况下将病毒载体递送至其治疗作用部位的方法。
