Joo Hyun-Yoo, Baek Hyunjung, Ahn Chun-Seob, Park Eun-Ran, Lee Youngju, Lee Sujung, Han Mihee, Kim Bora, Jang Yong-Hoon, Kwon Heechung
Gencellmed Inc., Korea Institute of Radiological and Medical Sciences, Room 302 Research Building #3, Seoul, Republic of Korea.
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Mol Ther Oncol. 2024 Feb 20;32(1):200778. doi: 10.1016/j.omton.2024.200778. eCollection 2024 Mar 21.
To retarget oncolytic herpes simplex virus (oHSV) to cancer-specific antigens, we designed a novel, double-retargeted oHSV platform that uses single-chain antibodies (scFvs) incorporated into both glycoprotein H and a bispecific adapter expressed from the viral genome to mediate infection predominantly via tumor-associated antigens. Successful retargeting was achieved using a nectin-1-detargeted HSV that remains capable of interacting with herpesvirus entry mediator (HVEM), the second canonical HSV entry receptor, and is, therefore, recognized by the adapter consisting of the virus-binding N-terminal 82 residues of HVEM fused to the target-specific scFv. We tested both an epithelial cell adhesion molecule (EpCAM)- and a human epidermal growth factor receptor 2-specific scFv separately and together to target cells expressing one, the other, or both receptors. Our results show not only dose-dependent, target receptor-specific infection , but also enhanced virus spread compared with single-retargeted virus. In addition, we observed effective infection and spreading of the EpCAM double-retargeted virus . Remarkably, a single intravenous dose of the EpCAM-specific virus eliminated all detectable tumors in a subcutaneous xenograft model, and the same intravenous dose seemed to be harmless in immunocompetent FVB/N mice. Our findings suggest that our double-retargeted oHSV platform can provide a potent, versatile, and systemically deliverable class of anti-cancer therapeutics that specifically target cancer cells while ensuring safety.
为了使溶瘤单纯疱疹病毒（oHSV）重新靶向癌症特异性抗原，我们设计了一种新型的双靶向oHSV平台，该平台使用整合到糖蛋白H和从病毒基因组表达的双特异性衔接子中的单链抗体（scFv），主要通过肿瘤相关抗原介导感染。使用脱靶NECTIN-1的HSV实现了成功的重新靶向，该HSV仍能够与疱疹病毒进入介质（HVEM）相互作用，HVEM是第二个经典的HSV进入受体，因此，由与靶标特异性scFv融合的HVEM的病毒结合N端82个残基组成的衔接子可识别该HSV。我们分别和共同测试了上皮细胞粘附分子（EpCAM）特异性和人表皮生长因子受体2特异性scFv，以靶向表达一种、另一种或两种受体的细胞。我们的结果不仅显示了剂量依赖性、靶标受体特异性感染，而且与单靶向病毒相比，病毒传播增强。此外，我们观察到EpCAM双靶向病毒的有效感染和传播。值得注意的是，在皮下异种移植模型中，单次静脉注射EpCAM特异性病毒消除了所有可检测到的肿瘤，并且相同的静脉注射剂量在具有免疫活性的FVB/N小鼠中似乎是无害的。我们的研究结果表明，我们的双靶向oHSV平台可以提供一类强效、通用且可全身递送的抗癌治疗药物，这些药物可特异性靶向癌细胞，同时确保安全性。
