Abstract：
:Two internalizing monovalent single chain antibody fragments (scFv), C6.5 and F5, that recognize distinct ErbB2 extracellular domain (ECD) epitopes, and their bivalent forms dbC6.5 and F5(scFv')(2), were compared to the growth-inhibiting anti-ErbB2 antibody Herceptin/trastuzumab, in either its bivalent (Her) or monovalent (4D5Fab') form, for their abilities to induce biological responses in the ErbB2-overexpressing breast cancer cells, SkBr-3. Assays compared internalization by receptor-mediated endocytosis, effects on cell cycling and culture growth, and interference with intracellular MAPK and PI3K signaling pathways. We found no correlation between ErbB2 epitope affinity or valency on degree of antibody-induced endocytosis, since all the scFv were able to internalize better than Her. Unlike Her, neither the monovalent or bivalent forms of the internalizing scFv had any sustained effect on cell growth. Basal levels of MAPK and PI3K signaling in SkBr-3 cells were not inhibited by up to 8 h scFv treatment, while decreased MAPK and PI3K signals were noted within 8 h of Her treatment. In summary, antibody-induced ErbB2-mediated endocytosis is not a surrogate marker for resultant biological response, as it shows no correlation with cell cycle, culture proliferation, or intracellular kinase signal induction by internalizing antibodies. Thus, the enhanced endocytotic property of scFv like C6.6 and F5 in conjunction with their absence of any growth or signaling impact on ErbB2-overexpressing cells favors their choice as ErbB2 targeting moieties for intracellular delivery of novel cancer therapeutics.
journal_name
Biochem Biophys Res Communjournal_title
Biochemical and biophysical research communicationsauthors
Neve RM,Nielsen UB,Kirpotin DB,Poul MA,Marks JD,Benz CCdoi
10.1006/bbrc.2000.4104subject
Has Abstractpub_date
2001-01-12 00:00:00pages
274-9issue
1eissn
0006-291Xissn
1090-2104pii
S0006-291X(00)94104-4journal_volume
280pub_type
杂志文章abstract：:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds modulate various endocrine functions by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene transcription. In the present study, we investigated the effects of TCDD on testosterone signal tr...
journal_title：Biochemical and biophysical research communications
pub_type： 杂志文章
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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journal_title：Biochemical and biophysical research communications
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