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• W2040998421 abstract "Abstract The major route of iron uptake by cells occurs through transferrin receptor (TfR)–mediated endocytosis of diferric-charged plasma transferrin (holo-Tf). In this work, we pursued TfR antibodies as potential cancer therapeutics, characterizing human single-chain variable antibody fragments (scFv) specific for the human TfR isolated from a phage display library. We hypothesized that many of these antibodies would function as ligand mimetics because scFvs from the library were selected for binding and internalization into living cells. In support of this hypothesis, the anti-TfR scFvs identified were antagonists of TfR binding to holo-Tf, particularly two of the most potent antibodies, 3TF12 and 3GH7, which blocked the in vitro proliferation of a number of hematopoietic cancer cell lines. We optimized this activity of 3TF12 and 3GH7 by engineering 55-kDa bivalent antibody formats, namely, F12CH and H7CH, which could block cell proliferation with an IC50 of 0.1 μg/mL. We found that the mechanism of the scFv antibody cytotoxicity was unique compared with cytotoxic anti-TfR monoclonal antibodies that have been described, causing cell surface upregulation of TfR along with the inhibition of holo-Tf cell uptake and induction of cell death. In a nude mouse model of erythroleukemia, administration of F12CH reduced tumor growth. Together, our findings define a new class of fully human anti-TfR antibodies suitable for immunotherapy against tumors whose proliferation relies on high levels of TfR and iron uptake, such as acute lymphoid and myeloid leukemias. Cancer Res; 70(13); 5497–506. ©2010 AACR." @default.
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• W2040998421 date "2010-06-30" @default.
• W2040998421 modified "2023-10-14" @default.
• W2040998421 title "Development of Human Single-Chain Antibodies to the Transferrin Receptor that Effectively Antagonize the Growth of Leukemias and Lymphomas" @default.
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• W2040998421 doi "https://doi.org/10.1158/0008-5472.can-10-0938" @default.
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