Targeted therapy of gastrointestinal cancer using human anti-CEA antibody
| Project/Area Number |
17591421
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Fukuoka University (2006)
Sapporo Medical University (2005) |
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Principal Investigator |
TANAKA Toshihiro Fukuoka University, Medicine, Instructor, 医学部, 助手 (00398314)
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| Co-Investigator(Kenkyū-buntansha) |
HAMADA Hirofumi Fukuoka University, Medicine, Professor, 医学部, 教授 (00189614)
KUROKI Masahide Fukuoka University, Medicine, Professor, 医学部, 教授 (40122692)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | adenovirus / CEA / antibody / gastric cancer / gene therapy |
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| Research Abstract |
We constructed a fiber modified Ad5 vector (Adv-FZ33) in which an IgG-binding domain (Z33) derived from staphylococcal protein A was inserted into the HI loop of knob protein. We evaluated on both in vitro and in vivo levels the extent of retargeting towards and therapeutic effectiveness against CEA-positive gastric cancers when using the anti-CEA antibody complex with this modified vector. In vitro LacZ gene expression after infection with Adv-FZ33 vectors conjugated to anti-CEA mAb was approximately 20 times higher than that obtained with vector conjugated to the control mAb. We generated Ax3CAUP-FZ33, which is an Adv-FZ33 derivative vector expressing a therapeutic gene, namely E. coli uracil phosphoribosyltransferase (UPRT) which converts 5FU directly to 5-fluorouridine monophosphate. When conjugated with the anti-CEA mAb, Ax3CAUP-FZ33 enhanced the cytotoxicity of 5FU (19.7-fold in terms of IC_<50> values) against gastric cancer cells. Nextl, we examined the survival effects of Ax3U
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P-FZ33 conjugated with anti-CEA mAb plus 5FU in mice with peritoneal disseminated gastric cancer. The median survival time of the Ax3CAUP-FZ33/anti-CEA mAb/5FU group was significantly longer than those of the PBS and 5FU only treatment groups (p<0.01, versus PBS and 5FU only groups).
Furthermore, we examined which subtype of IgG was effective on gene delivery mediated by Adv-FZ33 and anti-CEA mAb. BIACORE analysis showed that human IgG1 and IgG4 had 1,000-fold higher affinity constants (Ka) for protein A compared with mouse IgG1, whereas only 10-fold higher than mouse IgG2a or IgG3. In CEA-expressing cells, the transgene expression using Adv-FZ33 and any subtype of anti-CEA human IgG was significantly increased compared with combinations of any type of virus-anti-CEA mouse IgG. Especially, human IgG4 mediated transduction efficiency showed 200-fold enhancements compared with mouse IgG1. We found that the reactivity of Ab and protein A played a key role in the Ab dependent gene delivery by Adv-FZ33. Less
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Report
(3 results)
Research Products
(22 results)
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[Journal Article] Bcl-xL gene transfer inhibits Bax translocation and prolongs cardiac cold preservation time in rat.2005
Author(s)
Huang J, Nakamura K, Ito Y, Uzuka T, Morikawa M, Hirai S, Tomihara K, Tanaka T, Masuta Y, Ishii K, Kato K, Hamada H
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Journal Title
Circulation 112(1)
Pages: 76-83
Related Report
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[Journal Article] Re-targeting of cytotoxic T lymphocytes and/or natural killer cells to CEA-expressing tumor cells with anti-CEA antibody activity.2005
Author(s)
Kuroki, Ma., Hachimine, K., Huang J., Shibaguchi, H., Kinugasa, T., Maekawa, S., Kuroki, Mo.
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Journal Title
Anticancer Res. 25(6)
Pages: 3725-3732
NAID
Related Report
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[Journal Article] Targeting of cancer gene therapy with antibodies or their genes against tumor-associated antigens.2005
Author(s)
Kuroki, Ma., Shibaguchi, H., Kuroki, Mo., Kinugasa, T., Hachimine, K., Enatsu, S., Maekawa, S., Huang, J., Zhao, J.
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Journal Title
Gene Ther.Mol.Biol. 9(A)
Pages: 107-112
Related Report
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