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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 CHEM , 13 (1) 7 - 15. 10.1021/bc000178a.

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Abstract

Locoregional and intratumoral administration of tumor necrosis factor alpha (TNFalpha) has been successful in obtaining inhibition or regression of tumor growth in the clinic. This potent antitumor activity of TNFalpha 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 TNFalpha in the tumor has been achieved. To address this, we have targeted TNFalpha using antitumor antibodies. We have used a genetic fusion of human recombinant TNFalpha with MFE-23, a single-chain Fv antibody fragment directed against carcinoembryonic antigen. MFE-23::TNFalpha 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 rhTNFalpha. Radiolabeled MFE-23::TNFalpha 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::TNFalpha will provide an effective means for systemically administered cancer therapy with TNFalpha.

Type: Article
Title: In vivo tumor delivery of a recombinant single-chain Fv::Tumor necrosis factor: A fusion protein
DOI: 10.1021/bc000178a
Keywords: FACTOR-ALPHA, XENOGRAFT MODEL, GENE-THERAPY, PHASE-I, ANTIBODY, CANCER, ANTIGEN, RADIOIMMUNOTHERAPY, VASCULATURE, COMBINATION
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/137339
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