Transduction Properties of Adenovirus Serotype 35 Vectors After Intravenous Administration Into Nonhuman Primates.

Adenovirus serotype 35 (Ad35) vectors have shown promise as effective gene delivery vehicles. However, the transduction profiles of Ad35 vectors in conventional mice allow only a limited estimation of transduction properties of these vectors, because the mouse analog of the subgroup B Ad receptor, CD46, is restricted to the testis. In order to assess the transduction properties of Ad35 vectors more completely, we performed transduction experiments using cynomolgus monkeys, which ubiquitously express CD46 in a pattern similar to that in humans. In vitro transduction experiments demonstrated that cultured cells from the cynomolgus monkey were efficiently transduced with Ad35 vectors. In contrast, after intravenous administration into live monkeys hardly any evidence of Ad35 vector-mediated transduction was found in any of the organs, although Ad35 vector genomes were detected in various organs. Less severe histopathological abnormalities were found in the Ad35 vector-infused monkeys than in the conventional Ad5 vector-injected monkeys. In the latter, serious tissue damage and inflammatory responses, such as hepatocyte necrosis and lymphatic hyperplasia in the colon, were induced. Both Ad35 and Ad5 vectors caused similar hematological changes (increase in CD3+ cells, and decrease in CD16+ cells and CD20+ cells) in peripheral blood cells. These results should provide valuable information for the clinical application of Ad35 vectors.

Sakurai F ，Nakamura SI ，Akitomo K ，Shibata H ，Terao K ，Kawabata K ，Hayakawa T ，Mizuguchi H ... -  《-》

Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates.

Sakurai F ，Nakamura S ，Akitomo K ，Shibata H ，Terao K ，Kawabata K ，Hayakawa T ，Mizuguchi H ... -  《-》

Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates.

Sakurai F ，Nakamura SI ，Akitomo K ，Shibata H ，Terao K ，Kawabata K ，Hayakawa T ，Mizuguchi H ... -  《-》

Adenovirus serotype 35 vector-induced innate immune responses in dendritic cells derived from wild-type and human CD46-transgenic mice: Comparison with a fiber-substituted Ad vector containing fiber proteins of Ad serotype 35.

Recently, much attention has focused on replication-incompetent adenovirus (Ad) vectors containing fiber proteins derived from species B Ad serotype 35 (Ad35) (Ad5F35) and Ad vectors fully constructed from Ad35 as vaccine vectors expressing antigens. However, differences in the transduction properties, including the induction of innate immunity, of Ad5F35 and Ad35 vectors have not been properly and fully examined, partly because the transduction properties of these Ad vectors should be evaluated using nonhuman primates or human CD46-transgenic (CD46TG) mice, which ubiquitously express the primary receptor of Ad35, human CD46, in a pattern similar to that of humans. In the present study, we evaluated innate immune responses of mouse dendritic cells (mDCs) derived from bone marrow cells of wild-type (WT) and CD46TG mice following transduction with Ad serotype 5 (Ad5), fiber-substituted Ad5F35, or Ad35 vectors. Ad5F35 and Ad35 vectors mediated more efficient transduction in mDCs derived from CD46TG mice (CD46TG-mDCs) than did Ad5 vectors. Upregulation of costimulatory molecules and inflammatory cytokine induction by Ad5F35 and Ad35 vectors were significantly higher than those by Ad5 vectors in CD46TG-mDCs. However, the induction properties of the innate immune responses were different between Ad5F35 and Ad35 vectors. Ad35 vectors induced higher levels of costimulatory molecule expression and inflammatory cytokine production than did Ad5F35 vectors in CD46TG-mDCs. Furthermore, intravenous administration of Ad35 vectors in WT and CD46TG mice resulted in higher levels of serum interleukin (IL)-6 and IL-12 compared with administration of Ad5F35 vectors, which exhibited almost mock-transduced levels of these inflammatory cytokines. This study indicates that innate immune responses by Ad35 and Ad5F35 vectors are distinct even although both Ad vectors recognize human CD46 as a receptor.

Sakurai F ，Nakashima K ，Yamaguchi T ，Ichinose T ，Kawabata K ，Hayakawa T ，Mizuguchi H ... -  《-》

Adenovirus serotype 35 vector-mediated transduction into human CD46-transgenic mice.

Sakurai F ，Kawabata K ，Koizumi N ，Inoue N ，Okabe M ，Yamaguchi T ，Hayakawa T ，Mizuguchi H ... -  《GENE THERAPY》