Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM

被引:101
作者
Haisma, HJ
Pinedo, HM
van Rijswijk, A
van der Muelen-Muileman, I
Sosnowski, BA
Ying, W
van Beusechem, VW
Tillman, BW
Gerritsen, WR
Curiel, DT
机构
[1] Free Univ Amsterdam Hosp, Dept Med Oncol, Gene Therapy Program, NL-1007 MB Amsterdam, Netherlands
[2] Univ Alabama Birmingham, Gene Therapy Program, Birmingham, AL USA
[3] Select Genet, San Diego, CA USA
关键词
adenovirus; gene transfer; targeting; adenocarcinoma;
D O I
10.1038/sj.gt.3300969
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The utility of adenoviral vectors for cancer therapy is limited due to their lack of specificity for tumor cells. In order to target adenovirus to tumor, the natural tropism of the adenovirus should be ablated and replaced by a tumor-specific binding domain. To this end, a neutralizing anti-fiber antibody conjugated to an anti-EpCAM antibody was created that targets the adenovirus to the EpCAM antigen present on tumor cells. The EpCAM antigen was chosen as the target because this antigen is highly expressed on a variety of adenocarcinomas of different origin such as breast, ovary, colon and lung, whereas EpCAM expression is limited in normal tissues. In these studies, the EpCAM-targeted adenovirus was shown to infect specifically cancer cell lines of different origin expressing EpCAM such as ovary, colon and head and neck. Gene transfer was blocked by excess anti-EpCAM antibody and dramatically reduced in EpCAM negative cell lines, thus showing the specificity of the EpCAM-targeted adenovirus. Importantly, infection with targeted adenovirus was independent of CAR, which is the natural receptor for adenovirus binding, since blocking of CAR with recombinant fiber knob did not affect infection with targeted adenovirus. Apart from the cancer cell lines, the efficacy of targeted viral infection was studied in freshly isolated primary human colon cancer cells. As colon cancer predominantly metastasizes to liver, and adenovirus has a high tropism for hepatocytes, we also sought to determine if the EpCAM-targeted adenovirus showed reduced infectivity of human liver cells. The bispecific antibody could successfully mediate gene transfer to primary human colon cancer cells, whereas it almost completely abolished infection of liver cells. This work thus demonstrates that EpCAM-targeted adenoviral vectors can be specifically directed to a wide variety of adenocarcinomas. This approach may prove to be useful for selective gene therapy of cancer.
引用
收藏
页码:1469 / 1474
页数:6
相关论文
共 16 条
[1]   Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5 [J].
Bergelson, JM ;
Cunningham, JA ;
Droguett, G ;
KurtJones, EA ;
Krithivas, A ;
Hong, JS ;
Horwitz, MS ;
Crowell, RL ;
Finberg, RW .
SCIENCE, 1997, 275 (5304) :1320-1323
[2]   Targeted gene delivery by tropism-modified adenoviral vectors [J].
Douglas, JT ;
Rogers, BE ;
Rosenfeld, ME ;
Michael, SI ;
Feng, MZ ;
Curiel, DT .
NATURE BIOTECHNOLOGY, 1996, 14 (11) :1574-1578
[3]  
EDWARDS DP, 1986, CANCER RES, V46, P1306
[4]   Construction and characterization of a fusion protein of single-chain anti-carcinoma antibody 323/A3 and human β-glucuronidase [J].
Haisma, HJ ;
Brakenhoff, RH ;
Van der Meulen-Muileman, I ;
Pinedo, HM ;
Boven, E .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 1998, 45 (05) :266-272
[5]   ADENOVIRUS-MEDIATED TRANSFER OF LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE ACUTELY ACCELERATES CHOLESTEROL CLEARANCE IN NORMAL MICE [J].
HERZ, J ;
GERARD, RD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (07) :2812-2816
[6]   Characterization of an adenovirus vector containing heterologous peptide epitope in the HI loop of the fiber knob [J].
Krasnykh, V ;
Dmitriev, I ;
Mikheeva, G ;
Miller, CR ;
Belousova, N ;
Curiel, DT .
JOURNAL OF VIROLOGY, 1998, 72 (03) :1844-1852
[7]  
Li WP, 1997, J IMMUNOL, V159, P763
[8]   ACTIVE SPECIFIC IMMUNOTHERAPY OF ESTABLISHED MICROMETASTASIS - EFFECT OF CRYOPRESERVATION PROCEDURES ON TUMOR-CELL IMMUNOGENICITY IN GUINEA-PIGS [J].
PETERS, LC ;
HANNA, MG .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1980, 64 (06) :1521-1525
[9]   RANDOMIZED TRIAL OF MONOCLONAL-ANTIBODY FOR ADJUVANT THERAPY OF RESECTED DUKES-C COLORECTAL-CARCINOMA [J].
RIETHMULLER, G ;
SCHNEIDERGADICKE, E ;
SCHLIMOK, G ;
SCHMIEGEL, W ;
RAAB, R ;
HOFFKEN, K ;
GRUBER, R ;
PICHLMAIER, H ;
HIRCHE, H ;
PICHLMAYR, R ;
BUGGISCH, P ;
WITTE, J ;
EIGLER, FW ;
FACKLERSCHWALBE, I ;
FUNKE, I ;
SCHMIDT, CG ;
SCHREIBER, H ;
SCHWEIBERER, L ;
EIBLEIBESFELDT, B .
LANCET, 1994, 343 (8907) :1177-1183
[10]   Use of a novel cross-linking method to modify adenovirus tropism [J].
Rogers, BE ;
Douglas, JT ;
Ahlem, C ;
Buchsbaum, DJ ;
Frincke, J ;
Curiel, DT .
GENE THERAPY, 1997, 4 (12) :1387-1392