Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells.
Conditionally replicating adenoviruses (CRAd's) feature selective replication in and killing of tumor cells. Initial clinical studies with relatively attenuated early generation agents have resulted in promising safety and efficacy data. Nevertheless, increased specificity may be advantageous for an emerging generation of infectivity-enhanced CRAd's. Further, increased specificity could translate into a larger tolerated dose. An approach for increasing specificity is dual control of E1A expression. We constructed six CRAd's featuring two variants of the cyclo-oxygenase 2 (cox2) promoter, combined with three versions of E1A. Transcriptional targeting was supplemented with transductional targeting utilizing the serotype 3 knob. In vivo and in vitro results suggest that cox2 can be utilized for enhancing the specificity of E1A deletion mutants and that combination with the Delta24 mutation increases specificity without reducing potency. Combination with Delta2-Delta24 was specific but somewhat attenuated. The promoter variants behaved similarly, although the longer 1,554-bp version displayed a trend for improved specificity. Transcriptional modifications were compatible with transductional targeting and resulted in up to 100,000-fold increase in the therapeutic window for Ad5/3cox2Ld24 vs wild-type adenovirus. Thus, the proposed triple-targeting strategy may be useful for increasing the safety and efficacy of adenoviral gene therapy for ovarian cancer.
Bauerschmitz
Gerd J
GJ
Department of Medicine, Division of Human Gene Therapy, Gene Therapy Center, University of Alabama at Birmingham, 35294, USA.
Guse
Kilian
K
Kanerva
Anna
A
Menzel
Artur
A
Herrmann
Isabell
I
Desmond
Renee A
RA
Yamamoto
Masato
M
Nettelbeck
Dirk M
DM
Hakkarainen
Tanja
T
Dall
Peter
P
Curiel
David T
DT
Hemminki
Akseli
A
D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D012703:Serotyping; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D051546:Cyclooxygenase 2