Hill Claudia, Grundy Megan, Bau Luca, Wallington Sheena, Balkaran Joel, Ramos Victor, Fisher Kerry, Seymour Len, Coussios Constantin, Carlisle Robert
Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK.
Grup d'Enginyeria de Materials, Institut Quimic de Sarria, Universitat Ramon Llull, Barcelona, Spain.
Mol Ther Oncolytics. 2021 Mar 17;21:47-61. doi: 10.1016/j.omto.2021.03.011. eCollection 2021 Jun 25.
Vaccinia virus (VV) is a powerful tool for cancer treatment with the potential for tumor tropism, efficient cell-to-cell spread, rapid replication in cancer cells, and stimulation of anti-tumor immunity. It has a well-defined safety profile and is being assessed in late-stage clinical trials. However, VV clinical utility is limited by rapid bloodstream neutralization and poor penetration into tumors. These factors have often restricted its route of delivery to intratumoral or intrahepatic artery injection and may impede repeat dosing. Chemical stealthing improves the pharmacokinetics of non-enveloped viruses, but it has not yet been applied to enveloped viruses such as VV. In the present study, amphiphilic polymer was used to coat VV, leading to reduced binding of a neutralizing anti-VV antibody (81.8% of polymer-coated VV [PCVV] staining positive versus 97.1% of VV [p = 0.0038]). Attachment of anti-mucin-1 (aMUC1) targeting antibody, to give aMUC1-PCVV, enabled binding of the construct to MUC1. In high MUC1 expressing CAPAN-2 cells, infection with PCVV was reduced compared to VV, while infection was restored with aMUC1-PCVV. Pharmacokinetics of aMUC1-PCVV, PCVV, and VV were evaluated. After intravenous (i.v.) injection of 1 × 10 viral genomes (VG) or 5 × 10 VG, circulation time for PCVV and aMUC1-PCVV was increased, with ~5-fold higher circulating dose at 5 min versus VV.
痘苗病毒（VV）是一种用于癌症治疗的强大工具，具有肿瘤嗜性、高效的细胞间传播、在癌细胞中快速复制以及刺激抗肿瘤免疫的潜力。它具有明确的安全性概况，正在进行后期临床试验。然而，VV的临床应用受到快速的血流中和以及对肿瘤渗透不良的限制。这些因素常常限制了其给药途径为瘤内或肝动脉注射，并且可能妨碍重复给药。化学隐身改善了非包膜病毒的药代动力学，但尚未应用于诸如VV的包膜病毒。在本研究中，使用两亲性聚合物包被VV，导致中和抗VV抗体的结合减少（聚合物包被的VV [PCVV]染色阳性率为81.8%，而VV为97.1% [p = 0.0038]）。连接抗粘蛋白-1（aMUC1）靶向抗体，得到aMUC1-PCVV，使构建体能够与MUC1结合。在高表达MUC1的CAPAN-2细胞中，与VV相比，PCVV感染减少，而aMUC1-PCVV可恢复感染。评估了aMUC1-PCVV、PCVV和VV的药代动力学。静脉注射1×10病毒基因组（VG）或5×10 VG后，PCVV和aMUC1-PCVV的循环时间增加，在5分钟时循环剂量比VV高约5倍。
