Efficient retroviral vector targeting of carcinoembryonic antigen-positive tumors.
Many gene therapy approaches require specific, efficient gene delivery to cells in vivo. To target colorectal tumors we fused a single-chain variable fragment (scFv) directed against carcinoembryonic antigen (CEA) to the amphotropic murine leukemia virus envelope. A proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two proteins. Following attachment to CEA, MMP cleavage of the envelope at the cell surface removed the scFv and proline-rich hinge, allowing transduction. This allowed selective targeting of CEA-positive cells in vivo after injection of producer cells at the site of the tumor, with up to 10% of cells within a CEA-positive tumor xenograft becoming transduced. Intraperitoneal injection of amphotropic producer cells resulted in transduction of cells in spleen, liver, and kidney, which was not detected when CEA-targeted producer cells were used. These results demonstrate the feasibility of using targeted retroviral vectors for in vivo gene delivery to tumors. Furthermore, the lack of transduction of host cells eliminates the risk of insertional mutagenesis leading to transformation of host hematopoietic cells.
Chowdhury
Simon
S
Department of Immunology and Molecular Pathology, Windeyer Institute, London W1T 2AH, UK.
Chester
Kerry A
KA
Bridgewater
John
J
Collins
Mary K
MK
Martin
Francisco
F
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000276:immunology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D009052:Leukemia Virus, Murine / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012190:Retroviridae / Q000235:genetics*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D002272:Carcinoembryonic Antigen; D004268:DNA-Binding Proteins; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D020782:Matrix Metalloproteinases; D011993:Recombinant Fusion Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D014759:Viral Envelope Proteins; C451184:MFE-23 protein, human; C494187:POU1F1 protein, human; C494185:Pou1f1 protein, mouse