Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs

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Heiniö , C , Sorsa , S , Siurala , M , Grönberg-Vähä-Koskela , S , Havunen , R , Haavisto , E , Koski , A , Hemminki , O , Zafar , S , Cervera-Carrascon , V , Munaro , E , Kanerva , A & Hemminki , A 2019 , ' Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs ' , Human Gene Therapy , vol. 30 , no. 6 , pp. 740-752 . https://doi.org/10.1089/hum.2018.240

Title: Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs
Author: Heiniö, Camilla; Sorsa, Suvi; Siurala, Mikko; Grönberg-Vähä-Koskela, Susanna; Havunen, Riikka; Haavisto, Elina; Koski, Anniina; Hemminki, Otto; Zafar, Sadia; Cervera-Carrascon, Victor; Munaro, Eleonora; Kanerva, Anna; Hemminki, Akseli
Contributor: University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Department of Pathology
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Research Programs Unit
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, TRIMM - Translational Immunology Research Program
University of Helsinki, Akseli Eetu Hemminki / Principal Investigator
University of Helsinki, Department of Oncology
Date: 2019-06-01
Language: eng
Number of pages: 13
Belongs to series: Human Gene Therapy
ISSN: 1043-0342
URI: http://hdl.handle.net/10138/309908
Abstract: After the discovery and characterization of the adenovirus in the 1950s, this prevalent cause of the common cold and other usually mild diseases has been modified and utilized in biomedicine in several ways. To date, adenoviruses are the most frequently used vectors and therapeutic (e.g., oncolytic) agents with a number of beneficial features. They infect both dividing and nondividing cells, enable high-level, transient protein expression, and are easy to amplify to high concentrations. As an important and versatile research tool, it is of essence to understand the limits and advantages that genetic modification of adenovirus vectors may entail. Therefore, a retrospective analysis was performed of adenoviral gene therapy constructs produced in the same laboratory with similar methods. The aim was to assess the impact of various modifications on the physical and functional titer of the virus. It was found that genome size (designed within "the 105% golden rule") did not significantly affect the physical titer of the adenovirus preparations, regardless of the type of transgene (e.g., immunostimulatory vs. other), number of engineered changes, and size of the mutated virus genome. One statistically significant exception was noted, however. Chimeric adenoviruses (5/3) had a slightly lower physical titer compared to Ad5-based viruses, although a trend for the opposite was true for functional titers. Thus, 5/3 chimeric viruses may in fact be appealing from a safety versus efficacy viewpoint. Armed viruses had lower functional and physical titers than unarmed viruses, while five genomic modifications started to decrease functional titer. Importantly, even highly modified armed viruses generally had good titers compatible with clinical testing. In summary, this paper shows the plasticity of adenovirus for various vector, oncolytic, and armed oncolytic uses. These results inform future generations of adenovirus-based drugs for human use. This information is directly transferable to academic laboratories and the biomedical industry involved in vector design and production optimization.
Subject: adenovirus
vector
gene therapy
cancer
oncolytic virus
ONCOLYTIC ADENOVIRUSES
OVARIAN-CANCER
DELIVERY
FIBER
INTERLEUKIN-2
STABILITY
RECEPTOR
VECTORS
TRANSDUCTION
MESOTHELIOMA
3111 Biomedicine
1184 Genetics, developmental biology, physiology
3122 Cancers
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