Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Molecular Therapy: Oncolytics

Maxine Bauzon¹  Terry Hermiston¹  Len W. Seymour²  Margaret R. Duffy²  Janet Lei²  Ying Di²  André Lieber³  Simon Alvis⁴  John Beadle⁴  Sam Illingworth⁴  Brian Champion⁴  Kerry Fisher⁴ 

[1] Coagulant Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA 94158, USA;Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA;PsiOxus Therapeutics Ltd., Abingdon OX14 4SD, UK;

关键词: enadenotucirev;    adenovirus;    oncolytic virotherapy;    preclinical model;    mouse model;   

DOI  :  10.1016/j.omto.2017.03.003

来源: DOAJ

【 摘 要 】

Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

【 授权许可】

Unknown