Linked Life Data

11145716

Source:http://linkedlifedata.com/resource/pubmed/id/11145716

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-1-26
pubmed:abstractText
We describe a two-stage preparation of chemically engineered Ab constructs, employing as modules Fab'gamma from mAb or rAb, and Fc from human normal IgG1. A multivalent, optionally multispecific F(ab')(n) core is formed in stage one, and one or more Fc modules added in stage two. Examples include bispecific Fab(2)Fc(2) (for simplicity, primes and Greek letters are omitted from names of final constructs) and trivalent Fab(3)Fc(2), which are designed to kill neoplastic cells. An essential element in the construction is the availability of the Fab' in two reduced forms, Fab'(-sulfhydryl (SH))(5) and Fab'-SH. The first is obtained by full reduction of the interchain disulfide bonds (SS) in the F(ab')(2) fragment of IgG. Fab'-SH is obtained by disulfide-interchange reactions on Fab'(-SH)(5), whereby the gamma-light SS is reconstituted, an unusual intrachain SS forms in the gamma-chain hinge, and one hinge SH remains. F(ab')(2) and F(ab')(3) cores are built using partially reduced modules, being given intermodular thioether links that resist reduction. These cores are then fully reduced, making available SH groups for addition of the Fcgamma modules. In the final constructs, all intermodular links embody tandem thioether bonds arising at hinge-region cysteines. Cytotoxic activities of representative constructs, and some enhancements deriving from multiple modules, are assessed. In guinea pigs, catabolism of Fab(2)Fc(2) yielded a t(1/2) similar to that of human IgG1, although the serum Fab(2)Fc(2) revealed some proteolytic breakdown not shown by the IgG1. Immunotherapy of a guinea-pig leukemia confirmed the ability of these constructs to kill target cells in vivo.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
166
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1320-6
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11145716-Animals, pubmed-meshheading:11145716-Antibody-Dependent Cell Cytotoxicity, pubmed-meshheading:11145716-Antineoplastic Agents, pubmed-meshheading:11145716-Burkitt Lymphoma, pubmed-meshheading:11145716-Dimerization, pubmed-meshheading:11145716-Disulfides, pubmed-meshheading:11145716-Dithiothreitol, pubmed-meshheading:11145716-Guinea Pigs, pubmed-meshheading:11145716-Humans, pubmed-meshheading:11145716-Immunoglobulin Fab Fragments, pubmed-meshheading:11145716-Immunoglobulin Fc Fragments, pubmed-meshheading:11145716-Immunoglobulin G, pubmed-meshheading:11145716-Injections, Intravenous, pubmed-meshheading:11145716-Mice, pubmed-meshheading:11145716-Neoplasm Transplantation, pubmed-meshheading:11145716-Protein Engineering, pubmed-meshheading:11145716-Recombinant Fusion Proteins, pubmed-meshheading:11145716-Reducing Agents, pubmed-meshheading:11145716-Sulfhydryl Compounds, pubmed-meshheading:11145716-Tumor Cells, Cultured
pubmed:year
2001
pubmed:articleTitle
Thioether-bonded constructs of Fab'gamma and Fc gamma modules utilizing differential reduction of interchain disulfide bonds.
pubmed:affiliation
Biological Sciences, University of North London, London, United Kingdom. Tenovus Research Laboratory, Southampton University Hospitals, Southampton, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't