Dai Zhoutong, Si Yao, Xiong Shengfeng, Li Ying, Ye Jiaqi, Gao Qinglei, Ma Ding, Jin Xin, Li Fei
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Gene Ther. 2025 Apr;32(4):418-436. doi: 10.1038/s41417-025-00884-x. Epub 2025 Mar 8.
KD01, a third-generation conditionally replicating adenovirus serotype 5 developed by our team, has approved by the China Center for Drug Evaluation (CDE) for Phase I clinical trials (NCT06552598). However, 60% seroprevalence of anti-Ad5 neutralizing antibodies is a major hurdle for Ad5-based oncolytic viruses. To address this issue, we developed oAd5/35-HF, a fourth-generation oncolytic adenovirus vector designed to enhance infection efficiency and evade pre-existing neutralizing antibodies (NABs). To achieve this, we introduced targeted capsid modifications, replacing hexon hypervariable regions (HVRs) 1 and 5 with those from adenovirus serotype 35 (Ad35), along with alterations to the fiber region. These combined modifications significantly improved infection efficiency, maintained high viral titers, and enabled the virus to resist NABs. This is the first report of replacing both the Ad5 hexon HVRs and fiber regions with those from Ad35 in an oncolytic adenovirus, resulting in potent antitumor activity across multiple cancer types, even in the presence of high NAB levels. The oAd5/35-HF backbone provides a versatile platform for developing new chimera oncolytic adenovirus and adenovirus vector-based vaccine.
KD01是我们团队研发的第三代条件性复制腺病毒血清型5，已获得中国国家药品监督管理局药品审评中心（CDE）批准进行I期临床试验（NCT06552598）。然而，60%的抗Ad5中和抗体血清阳性率是基于Ad5的溶瘤病毒面临的一个主要障碍。为了解决这个问题，我们开发了oAd5/35-HF，这是一种第四代溶瘤腺病毒载体，旨在提高感染效率并逃避预先存在的中和抗体（NABs）。为了实现这一目标，我们引入了靶向衣壳修饰，用腺病毒血清型35（Ad35）的六邻体高变区（HVRs）1和5替换Ad5的相应区域，并对纤维区域进行了改造。这些联合修饰显著提高了感染效率，维持了高病毒滴度，并使病毒能够抵抗NABs。这是首次在溶瘤腺病毒中用Ad35的六邻体HVRs和纤维区域替换Ad5的相应区域的报道，即使在高NAB水平存在的情况下，该病毒在多种癌症类型中也具有强大的抗肿瘤活性。oAd5/35-HF骨架为开发新型嵌合溶瘤腺病毒和基于腺病毒载体的疫苗提供了一个通用平台。
