Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single-chain Fv molecules in monovalent (sFv) and divalent [(sFv')2] forms exhibit highly specific tumor targeting in mice as a result of their small size and rapid systemic clearance. As a consequence, there is a rapid reversal of the sFv blood/tumor gradient, resulting in diminished retention of sFv species in tumors. In this report we investigate two distinct strategies, dose escalation and repetitive intravenous (i.v.) dosing, aiming to increase the absolute selective retention of radiolabeled anti-c-erbB-2 125I-741F8 (sFv')2 in c-erbB-2-overexpressing SK-OV-3 tumors in mice with severe combined immunodeficiency (SCID). A dose-escalation strategy was applied to single i.v. injections of 125I-741F8 (sFv')2. Doses from 50 micrograms to 1000 micrograms were administered without a significant decrease in tumor targeting or specificity. High doses resulted in large increases in the absolute retention of 125I-741F8 (sFv')2. For example, raising the administered dose from 50 micrograms to 1000 micrograms increased the tumor retention 24 h after injection from 0.46 microgram/g to 9.5 micrograms/g, and resulted in a net increase of greater than 9 micrograms/g. Over the same dose range, the liver retention rose from 0.06 microgram/g to 1 microgram/g, and resulted in a net increase of less than 1 microgram/g. The retention of 9.5 micrograms/g in tumor 24 h following the 1000-micrograms dose of (sFv')2 was comparable to that seen 24 h after a 50-micrograms dose of 125I-741F8 IgG, indicating that the use of large doses of (sFv')2 may partially offset their rapid clearance. When two doses were administered by i.v. injection 24 h apart, the specificity of delivery to tumor observed after the first dose was maintained following the second injection. Tumor retention of 125I-741F8 (sFv')2 was 0.32 microgram/g at 24 h and 0.22 micrograms/g at 48 h following a single injection of 20 micrograms, while 0.04 microgram/ml and 0.03 microgram/ml were retained in blood at the same assay times. After a second 20-micrograms injection at the 24-h assay time, tumor retention increased to 0.49 micrograms/g, and blood retention was 0.06 microgram/ml, at the 48-h point. These results suggest that multiple high-dose administrations of radiolabeled 741F8 (sFv')2 may lead to the selective tumor localization of therapeutic radiation doses.
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PMID:Optimization of in vivo tumor targeting in SCID mice with divalent forms of 741F8 anti-c-erbB-2 single-chain Fv: effects of dose escalation and repeated i.v. administration. 760 May 61

Chimeric receptors comprising of the T-cell receptor-zeta cytoplasmic signalling chain fused to an extracellular ligand-binding domain of a single-chain antibody (scFv) have served as effective tools for redirecting cytotoxic T lymphocytes (CTL) against tumour cells. In this report, we constructed a chimeric scFv/zeta gene composed of the variable regions of an HER-2/neu-specific monoclonal antibody (MAb) joined to the TCR-zeta chain. The scFv(anti-HER-2/neu)/zeta chimeric gene was successfully expressed as a functional surface receptor in the MD.45 CTL hybridoma (MD.45-HER/zeta). More importantly, the scFv(anti-HER-2/neu)/zeta receptor was functionally active, since it triggered cytokine secretion by the MD.45-HER/zeta cells upon recognition of HER-2/neu-positive (+) tumour cell lines, or primary tumour cells from patients with HER-2/neu(+) cancers. The MD.45-HER/zeta-transduced cells also lysed HER-2/neu(+) target cells in vitro with high specificity. We tested the antitumour efficacy of scFv(anti-HER-2/neu)/zeta expressing MD.45 cells in severe combined immunodeficiency disease mice/human and murine tumour models. The adoptively transferred MD.45-HER/zeta cells both slowed significantly the growth of human FM3 melanoma or murine ALC leukaemic cells both transfected to express HER-2/neu. Our data demonstrate the feasibility of redirecting MD.45 CTL with the scFv(anti-HER-2/neu)/zeta chimeric receptor to respond specifically against HER-2/neu expressing tumour cells in vitro and in vivo. Moreover, they make it likely that T cells transduced with the same chimeric gene might be utilised in the treatment of patients with HER-2/neu(+) tumours.
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PMID:Redirecting mouse T hybridoma against human breast and ovarian carcinomas: in vivo activity against HER-2/neu expressing cancer cells. 1269 99