Targeting non-human coronaviruses to human cancer cells using a bispecific single-chain antibody.
To explore the potential of using non-human coronaviruses for cancer therapy, we first established their ability to kill human tumor cells. We found that the feline infectious peritonitis virus (FIPV) and a felinized murine hepatitis virus (fMHV), both normally incapable of infecting human cells, could rapidly and effectively kill human cancer cells artificially expressing the feline coronavirus receptor aminopeptidase N. Also 3-D multilayer tumor spheroids established from such cells were effectively eradicated. Next, we investigated whether FIPV and fMHV could be targeted to human cancer cells by constructing a bispecific single-chain antibody directed on the one hand against the feline coronavirus spike protein--responsible for receptor binding and subsequent cell entry through virus-cell membrane fusion--and on the other hand against the human epidermal growth factor receptor (EGFR). The targeting antibody mediated specific infection of EGFR-expressing human cancer cells by both coronaviruses. Furthermore, in the presence of the targeting antibody, infected cancer cells formed syncytia typical of productive coronavirus infection. By their potent cytotoxicity, the selective targeting of non-human coronaviruses to human cancer cells provides a rationale for further investigations into the use of these viruses as anticancer agents.
Würdinger
T
T
Virology Division, Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, The Netherlands.
Verheije
M H
MH
Raaben
M
M
Bosch
B J
BJ
de Haan
C A M
CA
van Beusechem
V W
VW
Rottier
P J M
PJ
Gerritsen
W R
WR
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000235:genetics; D018826:CD13 Antigens / Q000235:genetics; D002415:Cats; D018352:Coronavirus Infections / Q000276:immunology / Q000378:metabolism; D016765:Coronavirus, Feline / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000276:immunology; D016766:Feline Infectious Peritonitis / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D006517:Murine hepatitis virus / Q000235:genetics; D009369:Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000276:immunology
D018033:Antibodies, Bispecific; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D066246:ErbB Receptors; D018826:CD13 Antigens