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In vivo tumor delivery of a recombinant single-chain Fv::Tumor necrosis factor: A fusion protein

Cooke, SP; Pedley, RB; Boden, R; Begent, RHJ; Chester, KA; (2002) In vivo tumor delivery of a recombinant single-chain Fv::Tumor necrosis factor: A fusion protein. Bioconjugate Chemistry , 13 (1) pp. 7-15. 10.1021/bc000178a.

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Abstract

Locoregional and intratumoral administration of tumor necrosis factor α (TNFα) has been successful in obtaining inhibition or regression of tumor growth in the clinic. This potent antitumor activity of TNFα has not yet been exploited as a systemic agent in cancer therapy, mainly due to high levels of toxicity to normal tissues before a therapeutic dose of TNFα in the tumor has been achieved. To address this, we have targeted TNFα using antitumor antibodies. We have used a genetic fusion of human recombinant TNFα with MFE-23, a single-chain Fv antibody fragment directed against carcinoembryonic antigen. MFE-23::TNFα fusion protein is isolated in high yields (28 mg/L) from bacterial inclusion bodies and purified to homogeneity by affinity chromatography. It is a 144 kDa trimer in native form and possesses the antigen-binding activity of the sFv and the cytotoxicity to both WEHI 164 and a human adenocarcinoma cell line (LoVo) of rhTNFα. Radiolabeled MFE-23::TNFα binds both human and mouse TNF receptor 1 in vitro and is able to localize effectively in nude (nu/nu) mice bearing human LS174T xenografts; tumor/tissue ratios of 21:1 and 60:1 are achieved 24 and 48 h after intravenous injection. These studies indicate that MFE-23::TNFα will provide an effective means for systemically administered cancer therapy with TNFα.

Type: Article
Title: In vivo tumor delivery of a recombinant single-chain Fv::Tumor necrosis factor: A fusion protein
DOI: 10.1021/bc000178a
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/28109
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