Species D Adenoviruses as Oncolytic Viral Vectors

Abstract

Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.

Engineering Cancer Selective Virotherapies: Are the Pieces of the Puzzle Falling into Place?

“…lysis of cells (in vitro and in vivo) 17 . HAdV-D 26, 28, 45 and 48 infect and replicate in several cancer cell lines, although cytotoxicity was lower than adenovirus 5-based vectors 18 .…”

“… 17 HAdV-D 26, 28, 45, and 48 have been shown to infect and replicate in several cancer cell lines, although cytotoxicity was lower than adenovirus 5-based vectors. 18 Moreover, a replication-competent species B Ad11-derived vector was demonstrated to be capable of infecting and inducing oncolysis in colon cancer cell lines, which expressed high levels of the CD46 receptor. 19 These studies highlight the feasibility of generating virotherapies from noncanonical human adenoviral serotypes.…”

Time-Resolved Studies of Ytterbium Distribution at Interfacial Surfaces of Ferritin-like Dps Protein Demonstrate Metal Uptake and Storage Pathways

“…Viruses and phages comprise highly symmetric protein cages which naturally enclose DNA or RNA [ 6 ]. These, being the largest CSPs of 65 nm diameter ( Figure 1 A), are often used for biomedical applications including vehicles for targeted anti-cancer therapy and templated nanoparticle synthesis [ 7 , 8 ]. Another smaller biomolecular capsid is encapsulin, found in many prokaryotic organisms.…”

“…Apo-encapsulin has been used for the formation of magnetic nanoparticles. In addition, medicines have also been enclosed, demonstrating the potential of this complex as a bio-imaging and medical therapy carrier [ 7 , 8 ].…”

“…Apo-encapsulin has been used for the formation of magnetic nanoparticles. In addition, medicines have also been enclosed, demonstrating the potential of this complex as a bio-imaging and medical therapy carrier [7,8]. Biomineralization in proteins of the ferritin superfamily (bacterioferritin, ferritin and Dps) is a multistep mechanism initiated by the electrostatic interaction of the positively charged iron atoms with residues surrounding the uptake pores of ferritin and Dps [3,10].…”