A conditionally replicating adenovirus with strict selectivity in killing cells expressing epidermal growth factor receptor.
Virotherapy of cancer using oncolytic adenoviruses has shown promise in both preclinical and clinical settings. One important challenge to reach the full therapeutic potential of oncolytic adenoviruses is accomplishing efficient infection of cancer cells and avoiding uptake by normal tissue through tropism modification. Towards this goal, we constructed and characterized an oncolytic adenovirus, carrying mutated capsid proteins to abolish the promiscuous adenovirus native tropism and encoding a bispecific adapter molecule to target the virus to the epidermal growth factor receptor (EGFR). The new virus displayed a highly selective targeting profile, with reduced infection of EGFR-negative cells and efficient killing of EGFR-positive cancer cells including primary EGFR-positive osteosarcoma cells that are refractory to infection by conventional adenoviruses. Our method to modify adenovirus tropism might thus be useful to design new oncolytic adenoviruses for more effective treatment of cancer.
Carette
Jan E
JE
Department of Medical Oncology, Gene Therapy Division, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Graat
Harm C A
HC
Schagen
Frederik H E
FH
Mastenbroek
D C Jeroen
DC
Rots
Marianne G
MG
Haisma
Hidde J
HJ
Groothuis
Geny M M
GM
Schaap
Gerard R
GR
Bras
Johannes
J
Kaspers
Gertjan J L
GJ
Wuisman
Paul I J M
PI
Gerritsen
Winald R
WR
van Beusechem
Victor W
VW
D000256:Adenoviridae / Q000502:physiology*; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D018033:Antibodies, Bispecific / Q000276:immunology / Q000378:metabolism; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D011485:Protein Binding; D013045:Species Specificity; D014779:Virus Replication
D000906:Antibodies; D018033:Antibodies, Bispecific; D000914:Antibodies, Viral; D036022:Capsid Proteins; D007135:Immunoglobulin Variable Region; C018315:hexon capsid protein, Adenovirus; D066246:ErbB Receptors