Design and Selection of Toca 511 for Clinical Use: Modified Retroviral Replicating Vector With Improved Stability and Gene Expression

Autor: Taylor Buckley, Kei Hiraoka, Ryan Burnett, Akihito Inagaki, Christopher R. Logg, Cindy Burrascano, Douglas J. Jolly, Carlos E. Ibanez, Daniel L. Lohse, Karin Kristina Amundson, Dawn Jolson, Oscar Diago, Noriyuki Kasahara, Amy Lin, Omar D. Perez, Harry E. Gruber
Rok vydání: 2012
Předmět:
RNA Stability
Flucytosine
Gene Expression
Cytosine Deaminase
Mice
0302 clinical medicine
Interferon
Gene expression
Drug Discovery
Murine leukemia virus
Prodrugs
Transgenes
Vector (molecular biology)
Genetics
0303 health sciences
biology
Cytosine deaminase
Molecular therapy
3. Good health
Leukemia Virus
Murine
030220 oncology & carcinogenesis
Molecular Medicine
Original Article
Fluorouracil
Corrigendum
medicine.drug
Vocimagene Amiretrorepvec
Transgene
Genetic Vectors
Stability (learning theory)
Antineoplastic Agents
Virus
Fungal Proteins
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Molecular Biology
Selection (genetic algorithm)
030304 developmental biology
Pharmacology
Genetic Therapy
Neoplasms
Experimental
biology.organism_classification
Virology
Rats
Oncolytic virus
Neoplasm Transplantation
Zdroj: Molecular Therapy. 20:1689-1698
ISSN: 1525-0016
Popis: Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic replicating viruses as anticancer agents, being selective both for dividing cells and for cells that have defects in innate immunity and interferon responsiveness. Tumor cells fit both these descriptions. Previous publications have described a prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report here the selection of one lead clinical candidate based on a general design goal to optimize the genetic stability of the virus and the CD activity produced by the delivered transgene. Vectors were tested for titer, genetic stability, CD protein and enzyme activity, ability to confer susceptibility to 5-FC, and preliminary in vivo antitumor activity and stability. One vector, Toca 511, (aka T5.0002) encoding an optimized CD, shows a threefold increased specific activity in infected cells over infection with the prototype RRV and shows markedly higher genetic stability. Animal testing demonstrated that Toca 511 replicates stably in human tumor xenografts and, after 5-FC administration, causes complete regression of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward to preclinical and clinical trials.
Databáze: OpenAIRE
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