Antibodies against adenovirus fiber and penton base proteins inhibit adenovirus vector-mediated transduction in the liver following systemic administration.
Antibodies against adenovirus fiber and penton base proteins inhibit adenovirus vector-mediated transduction in the liver following systemic administration.
复制标题
DOI：
10.1038/s41598-018-30947-z
复制
发表时间：
2018-08-17
影响因子：
4.6
通讯作者：
Mizuguchi H
中科院分区：
文献类型：
--
作者：
Tomita K;Sakurai F;Iizuka S;Hemmi M;Wakabayashi K;Machitani M;Tachibana M;Katayama K;Kamada H;Mizuguchi H
预先存在的抗腺病毒（Ad）中和抗体（AdNAb）是使用Ad载体和溶瘤Ad的临床基因治疗中的主要障碍;然而，尚未完全阐明哪种Ad衣壳蛋白特异性抗体参与AdNAb介导的体内Ad感染抑制。在本研究中，通过肌内电穿孔每个Ad衣壳蛋白表达质粒，制备具有对每个Ad衣壳蛋白特异性的抗体的小鼠。在用纤维蛋白表达质粒或五邻体碱基表达质粒免疫的小鼠中，Ad载体介导的肝转导被有效地抑制超过100倍。在施用前用FX预包被的Ad载体介导的用纤维蛋白表达质粒或五邻体碱基表达质粒免疫的华法林化小鼠的肝脏中的转导效率比未免疫的华法林化小鼠的肝脏中的转导效率低100倍以上。这些数据表明，抗纤维蛋白和抗五邻体基础抗体结合到Ad载体，即使FX已经结合到六邻体，并抑制Ad载体介导的转导。本研究为开发一种新的能够规避AdNAbs抑制作用的Ad载体提供了重要线索。
Pre-existing anti-adenovirus (Ad) neutralizing antibodies (AdNAbs) are a major barrier in clinical gene therapy using Ad vectors and oncolytic Ads; however, it has not been fully elucidated which Ad capsid protein-specific antibodies are involved in AdNAb-mediated inhibition of Ad infection in vivo. In this study, mice possessing antibodies specific for each Ad capsid protein were prepared by intramuscular electroporation of each Ad capsid protein-expressing plasmid. Ad vector-mediated hepatic transduction was efficiently inhibited by more than 100-fold in mice immunized with a fiber protein-expressing plasmid or a penton base-expressing plasmid. An Ad vector pre-coated with FX before administration mediated more than 100-fold lower transduction efficiencies in the liver of warfarinized mice immunized with a fiber protein-expressing plasmid or a penton base-expressing plasmid, compared with those in the liver of warfarinized non-immunized mice. These data suggest that anti-fiber protein and anti-penton base antibodies bind to an Ad vector even though FX has already bound to the hexon, and inhibit Ad vector-mediated transduction. This study provides important clues for the development of a novel Ad vector that can circumvent inhibition with AdNAbs.
登录
查看更多内容
影响因子：
64.5
作者：
CEPKO, CL;SHARP, PA
通讯作者：
SHARP, PA
影响因子：
5.4
作者：
Bradley, Ritu R.;Maxfield, Lori F.;Barouch, Dan H.
通讯作者：
Barouch, Dan H.
在晚期结直肠癌中，对剂量，安全性，免疫原性和总体生存的1/2期试验进行了扩展评估。
DOI：
10.1007/s00262-015-1706-4
发表时间：
2015-08
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Balint JP;Gabitzsch ES;Rice A;Latchman Y;Xu Y;Messerschmidt GL;Chaudhry A;Morse MA;Jones FR
通讯作者：
Jones FR
影响因子：
4.2
作者：
Koizumi, N;Kawabata, K;Mizuguchi, H
通讯作者：
Mizuguchi, H
影响因子：
5.4
作者：
Koizumi, N;Mizuguchi, H;Hayakawa, T
通讯作者：
Hayakawa, T