Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter.
Adenovirus vectors have a number of advantages for gene therapy. However, because of their lack of tumor tropism and their preference for liver infection following systemic administration, they cannot be used for systemic attack on metastatic disease. Many epithelial tumors (e.g., colon, lung, and breast) express carcinoembryonic antigen (CEA). To block the natural hepatic tropism of adenovirus and to "retarget" the virus to CEA-expressing tumors, we used a bispecific adapter protein (sCAR-MFE), which fuses the ectodomain of the coxsackie/adenovirus receptor (sCAR) with a single-chain anti-CEA antibody (MFE-23). sCAR-MFE untargets adenovirus-directed luciferase transgene expression in the liver by >90% following systemic vector administration. Moreover, sCAR-MFE can "retarget" adenovirus to CEA-positive epithelial tumor cells in cell culture, in s.c. tumor grafts, and in hepatic tumor grafts. The sCAR-MFE bispecific adapter should, therefore, be a powerful agent to retarget adenovirus vectors to epithelial tumor metastases.
Li
Hua-Jung
HJ
Department of Biological Chemistry, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA.
Everts
Maaike
M
Pereboeva
Larisa
L
Komarova
Svetlana
S
Idan
Anat
A
Curiel
David T
DT
Herschman
Harvey R
HR
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007128:Immunoglobulin Fragments / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D011991:Receptors, Virus / Q000096:biosynthesis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D002272:Carcinoembryonic Antigen; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007128:Immunoglobulin Fragments; C451184:MFE-23 protein, human; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins