Polymer stealthing and mucin-1 retargeting for enhanced pharmacokinetics of an oncolytic vaccinia virus

Abstract

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 8 viral genomes (VG) or 5 × 10 8 VG, circulation time for PCVV and aMUC1-PCVV was increased, with ~5-fold higher circulating dose at 5 min versus VV.

The employment of vaccinia virus for colorectal cancer treatment: A review of preclinical and clinical studies

“…Polymeric materials have been developed to reduce neutralizing anti-VV antibody and promote tumor tropism. 92 These results may suggest an important direction for VV development. Although the safety of VV has been validated in many human clinical trials, attentions need be paid to the biosafety and risk of the therapies based on VV.…”

“…Polymeric materials have been developed to reduce neutralizing anti-VV antibody and promote tumor tropism. 92 These results may suggest an important direction for VV development.…”

Oncolytic Virus Engineering and Utilizations: Cancer Immunotherapy Perspective

“…Chemical delivery methods include the use of chemical-based polymers such as PEG, hydrogels (natural and synthetic), nano-biomaterial-based metal nanoparticles, liposomes, polymeric micelles, and biological carriers such as stem cells, natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells; however, few delivery approaches were tested in clinical trials [ 130 , 131 , 132 , 133 , 134 , 135 ]. Physical methods include magnetic nanoparticle-encapsulated OV delivery, which effectively enhances the infection rate, leading to tumor suppression [ 136 , 137 ].…”

Emerging systemic delivery strategies of oncolytic viruses: A key step toward cancer immunotherapy

“…Owing to excellent biocompatibility and stability, polymer nanocarriers have been used in drug delivery. For example, considering the electrostatic interaction between the positively charged agmatine block and the negatively charged adenoviral capsid surface, Mariangela Garofalo et al encapsulated OVs into a polygalactosyl-b-agmatyl diblock copolymer (Gal32-b-Agm29) for hepatocellular carcinoma (HCC) remedy, which has high affinity for the asialoglycoprotein receptor (ASGPR) expressed on the liver cell surface [93]. Moreover, Robert Carlisle et al used cholesterol-PEG polymers and anti-MUC1 (aMUC1) antibodies to provide the coating and targeting for an VV to cellular mucin-1 (MUC1) [94].…”