Linked Life Data

10582696

Source:http://linkedlifedata.com/resource/pubmed/id/10582696

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
1999-12-14
pubmed:abstractText
The epithelial glycoprotein-2 is abundantly expressed on many solid tumors and is a suitable target for antibody-based therapy. In the present study, an antiepithelial glycoprotein-2 single-chain Fv (scFv) was derived from the hybridoma MOC31 by phage display. Despite its high affinity (KD = 3.9 x 10(-9) M), however, this antibody fragment failed to significantly enrich at lung tumor xenografts in mice, mostly because of its insufficient thermal stability. To overcome this limitation, the antigen-binding residues of the MOC31 scFv fragment were grafted onto the framework of the highly stable and well-folding anti-c-erbB2 scFv 4D5. Further modification of the resulting 4D5 MOC-A, which was performed by transferring eight additional residues of the heavy chain variable domain core of the parent MOC31 antibody, produced 4D5 MOC-B, resulting in increased serum stability at 37 degrees C and also significantly improved expression behavior while retaining the antigen specificity and affinity of the parent MOC31 scFv. In mice, the scFv 4D5 MOC-B, which was radiolabeled with 99mtechnetium using a new histidine-tag specific labeling method (Waibel et al., Nature Biotechnol., 17: 897-901, 1999), showed favorable blood clearance and efficient enriches at lung tumor xenografts, with a tumor:blood ratio of 5.25 and a total dose of 1.47% injected dose per gram after 24 h. Biophysical properties such as high thermal stability are thus decisive for whether these molecules are useful in vivo, and our approach may provide a general strategy to solve this problem. This is also the first report of using a humanized anti-EGP-2 scFv in vivo for targeting solid tumors, which is a promising targeting moiety for the diagnostics and therapy of EGP-2-positive tumors in patients.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
59
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5758-67
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:10582696-Amino Acid Sequence, pubmed-meshheading:10582696-Animals, pubmed-meshheading:10582696-Antibodies, Neoplasm, pubmed-meshheading:10582696-Antibody Specificity, pubmed-meshheading:10582696-Antigens, Neoplasm, pubmed-meshheading:10582696-Cell Adhesion Molecules, pubmed-meshheading:10582696-Female, pubmed-meshheading:10582696-Hot Temperature, pubmed-meshheading:10582696-Humans, pubmed-meshheading:10582696-Immunoglobulin Fragments, pubmed-meshheading:10582696-Immunoglobulin Variable Region, pubmed-meshheading:10582696-Isotope Labeling, pubmed-meshheading:10582696-Mice, pubmed-meshheading:10582696-Mice, Inbred BALB C, pubmed-meshheading:10582696-Mice, Nude, pubmed-meshheading:10582696-Models, Chemical, pubmed-meshheading:10582696-Molecular Sequence Data, pubmed-meshheading:10582696-Protein Structure, Secondary, pubmed-meshheading:10582696-Receptor, erbB-2, pubmed-meshheading:10582696-Sequence Alignment, pubmed-meshheading:10582696-Technetium, pubmed-meshheading:10582696-Tumor Cells, Cultured
pubmed:year
1999
pubmed:articleTitle
High thermal stability is essential for tumor targeting of antibody fragments: engineering of a humanized anti-epithelial glycoprotein-2 (epithelial cell adhesion molecule) single-chain Fv fragment.
pubmed:affiliation
Department of Biochemistry, University of Zürich, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't