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 |
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Authors: | Gregory P. Adams John E. McCartney Ellen J. Wolf Jamie Eisenberg Mei-Sheng Tai James S. Huston Walter F. Stafford III Michael A. Bookman L. L. Houston Louis M. Weiner |
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Affiliation: | (1) Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, 19111 Philadelphia, PA, USA;(2) Cetus Oncology Corp, 94608 Emeryville, CA, USA;(3) Creative BioMolecules Inc., 01748 Hopkinton, MA, USA;(4) Boston Biomedical Research Institute, 02114 Boston, MA, USA;(5) Present address: Prizin Pharmaceuticals Inc., 92121 San Diego, CA, USA |
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Abstract: | 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-2125I-741F8 (sFv')2 in c-erbB-2-overexpressing SK-OV-3 tumors in mice with severe combined immunodeficiency (SCID). A doseescalation strategy was applied to single i.v. injections of125I-741F8 (sFv')2. Doses from 50 g to 1000 g were administered without a significant decrease in tumor targeting or specificity. High doses resulted in large increases in the absolute retention of125I-741F8 (sFv')2. For example, raising the administered dose from 50 g to 1000 g increased the tumor retention 24 h after injection from 0.46 g/g to 9.5 g/g, and resulted in a net increase of greater than 9 /g. Over the same dose range, the liver retention rose from 0.06 g/g to 1 g/g, and resulted in a net increase of less than 1 g/g. The retention of 9.5 g/g in tumor 24 h fllowing the 1000-g dose of (sFv')2 was comparable to that seen 24 h after a 50-g dose of125I-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 of125I-741F8 (sFv')2 was 0.32 g/g at 24 h and 0.22 g/g at 48 h following a single injection of 20 g/g, while 0.04 g/ml and 0.03 g/ml were retained in blood at the same assay times. After a second 20-g injection at the 24-h assay time, tumor retention increased to 0.49 g/g, and blood retention was 0.06 g/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.Supported by National Cancer Institute (NCI) National Cooperative Drug Discovery Group grant U01 CA51880, CA06927, an appropriation from the Commonwealth of Pennsylvania, and the Bernard A. and Rebecca S. Bernard Foundation |
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Keywords: | Single-chain Fv molecules Dose Immunotargeting c-erbB-2 Specificity |
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