Development of a low-seroprevalence, αvβ6 integrin-selective virotherapy based on human adenovirus type 10

Bates, Emily A.; Davies, James A.; Váňová, Jana; Nestić, Davor; Méniel, Valérie S.; Koushyar, Sarah; Cunliffe, Tabitha G.; Mundy, R.M.; Moses, Elise; Uusi-Kerttula, Hanni; Baker, Alex; Cole, David K.; Majhen, Dragomira; Rizkallah, P.J.; Phesse, Toby J.; Chester, John D.; Parker, Alan L.

doi:10.1016/j.omto.2022.03.007

Cited by 10 publications

(12 citation statements)

References 56 publications

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“…The final published version may differ from this proof. 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 .…”

Section: Capsid Engineering: Capitalising Upon Natural Viral Variationmentioning

confidence: 99%

“…The species D adenovirus serotype 10 (HAdV-D10, Ad10) has recently been shown to form weak interactions with known adenoviral receptors, therefore providing a compelling starting point for engineering more cell type-selective infection and lysis of cells ( in vitro and in vivo ). 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.…”

Section: Cell Extrinsic Options For Gaining Selectivitymentioning

confidence: 99%

“… 49 , 50 Homology modeling has revealed the DG loop of the Species D adenoviruses 10 and 48 to be similarly permissive to insert engineering. 17 , 51 , 52 The C-terminus of the HAdV-C5 knob domain has also previously been shown to enable virus re-targeting without compromising capsid assembly, 53 while another approach has been to remove the fiber knob entirely and replace this with domains that facilitate incorporation of larger targeting molecules without structural clashing such as the T4 bacteriophage-derived fibritin protein. 54 …”

Section: Cell Extrinsic Options For Gaining Selectivitymentioning

confidence: 99%

See 2 more Smart Citations

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

2022

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Section: Capsid Engineering: Capitalising Upon Natural Viral Variationmentioning

confidence: 99%

Section: Cell Extrinsic Options For Gaining Selectivitymentioning

confidence: 99%

Section: Cell Extrinsic Options For Gaining Selectivitymentioning

confidence: 99%

See 1 more Smart Citation

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

2022

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“…Neutralising antibodies against Ad5, generated in response to a natural pathogenic infection, may hamper the efficacy of Ad5 based therapies when deployed clinically due to immune inactivation [9], [10]. Alternative serotypes including Ad10 have been explored to overcome the effects of anti-Ad5 neutralization [11]. In addition, Ad5 engages coxsackie and adenovirus receptor (CAR) [12] as a primary means of cell entry, a receptor that is expressed both on erythrocytes and the tight junctions of epithelial cells (reviewed in [13]), yet is commonly downregulated by some types of cancer [14], [15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, sialic acid is known to be expressed at high levels in the brain [24] . We have also shown that GBM does not express αvβ6 integrin, which is upregulated in many other types of aggressive cancers (e.g., ovarian, lung, skin and cervical cancer [25], and is a promising target for novel adenoviral oncolytic therapies [11], [26]- [28]. We also investigated the efficacy of various Ad5 pseudotypes to gauge which adenoviral serotype may be better suited for oncolytic therapy in GBM.…”

Section: Introductionmentioning

confidence: 99%

Engineering Adenoviral Vectors With Improved GBM Selectivity

Bates¹,

Lovatt²,

Plein³

et al. 2023

Preprint

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Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

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Structural analysis of peptide binding to integrins for cancer detection and treatment

Urquiza,

Benavides-Rubio,

Jimenez-Camacho

2023

Biophys Rev

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Integrins are cell receptors involved in several metabolic pathways often associated with cell proliferation. Some of these integrins are downregulated during human physical development, but when these integrins are overexpressed in adult humans, they can be associated with several diseases, such as cancer. Molecules that specifically bind to these integrins are useful for cancer detection, diagnosis, and treatment. This review focuses on the structures of integrin-peptidic ligand complexes to dissect how the binding occurs and the molecular basis of the specificity and affinity of these peptidic ligands. Understanding these interactions at the molecular level is fundamental to be able to design new peptides that are more specific and more sensitive to a particular integrin. The integrin complexes covered in this review are α5β1, αIIbβ3, αvβ3, αvβ6, and αvβ8, because the molecular structures of the complex have been experimentally determined and their presence on tumor cancer cells are associated with a poor prognosis, making them targets for cancer detection and treatment.

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Development of a low-seroprevalence, αvβ6 integrin-selective virotherapy based on human adenovirus type 10

Cited by 10 publications

References 56 publications

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

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

Engineering Adenoviral Vectors With Improved GBM Selectivity

Structural analysis of peptide binding to integrins for cancer detection and treatment

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