Source:http://linkedlifedata.com/resource/pubmed/id/16778135
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2006-7-7
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| pubmed:abstractText |
Platelet activation causes conformational changes of integrin GPIIb/IIIa (alpha(IIb)beta3), resulting in the exposure of its ligand-binding pocket. This provides the unique possibility to design agents that specifically block activated platelets only. We used phage display of single-chain antibody (scFv) libraries in combination with several rounds of depletion/selection to obtain human scFvs that bind specifically to the activated conformation of GPIIb/IIIa. Functional evaluation of these scFv clones revealed that fibrinogen binding to human platelets and platelet aggregation can be effectively inhibited by activation-specific scFvs. In contrast to clinically used GPIIb/IIIa blockers, which are all conformation unspecific, activation-specific GPIIb/IIIa blockers do not induce conformational changes in GPIIb/IIIa or outside-in signaling, as evaluated by ligand-induced binding-site (LIBS) exposure in flow cytometry or P-selectin expression in immunofluorescence microscopy, respectively. In contrast to the conformation-unspecific blocker abciximab, activation-specific scFvs permit cell adhesion and spreading on immobilized fibrinogen, which is mediated by nonactivated GPIIb/IIIa. Mutagenesis studies and computer modeling indicate that exclusive binding of activation-specific scFv is mediated by RXD motifs in the heavy-chain complementary-determining region (CDR) 3 of the antibodies, which in comparison with other antibodies forms an exceptionally extended loop. In vivo experiments in a ferric-chloride thrombosis model of the mouse carotid artery demonstrate similar antithrombotic potency of activation-specific scFv, when compared with the conformation-unspecific blockers tirofiban and eptifibatide. However, in contrast to tirofiban and eptifibatide, bleeding times are not prolonged with the activation-specific scFvs, suggesting lower bleeding risks. In conclusion, activation-specific GPIIb/IIIa blockade via human single-chain antibodies represents a promising novel strategy for antiplatelet therapy.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies,
http://linkedlifedata.com/resource/pubmed/chemical/Chlorides,
http://linkedlifedata.com/resource/pubmed/chemical/Complementarity Determining Regions,
http://linkedlifedata.com/resource/pubmed/chemical/Ferric Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Fibrinogen,
http://linkedlifedata.com/resource/pubmed/chemical/Fibrinolytic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Aggregation Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Glycoprotein GPIIb-IIIa...,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/eptifibatide,
http://linkedlifedata.com/resource/pubmed/chemical/ferric chloride,
http://linkedlifedata.com/resource/pubmed/chemical/tirofiban
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
1524-4571
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| pubmed:author |
pubmed-author:AhrensIngoI,
pubmed-author:BasslerNicoleN,
pubmed-author:BodeChristophC,
pubmed-author:ChenYung ChihYC,
pubmed-author:FitzgeraldDesmondD,
pubmed-author:HagemeyerChristoph ECE,
pubmed-author:KennyDermotD,
pubmed-author:MeadeGerardeneG,
pubmed-author:MoranNiamhN,
pubmed-author:PeterKarlheinzK,
pubmed-author:SchwarzMeikeM,
pubmed-author:StollPatrickP,
pubmed-author:YlanneJariJ
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| pubmed:issnType |
Electronic
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| pubmed:day |
7
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| pubmed:volume |
99
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
25-33
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:16778135-Amino Acid Motifs,
pubmed-meshheading:16778135-Animals,
pubmed-meshheading:16778135-Antibodies,
pubmed-meshheading:16778135-Bleeding Time,
pubmed-meshheading:16778135-Blood Platelets,
pubmed-meshheading:16778135-Carotid Artery Diseases,
pubmed-meshheading:16778135-Chlorides,
pubmed-meshheading:16778135-Complementarity Determining Regions,
pubmed-meshheading:16778135-Ferric Compounds,
pubmed-meshheading:16778135-Fibrinogen,
pubmed-meshheading:16778135-Fibrinolytic Agents,
pubmed-meshheading:16778135-Humans,
pubmed-meshheading:16778135-Mice,
pubmed-meshheading:16778135-Mice, Inbred C57BL,
pubmed-meshheading:16778135-Molecular Conformation,
pubmed-meshheading:16778135-Peptides,
pubmed-meshheading:16778135-Platelet Activation,
pubmed-meshheading:16778135-Platelet Aggregation Inhibitors,
pubmed-meshheading:16778135-Platelet Glycoprotein GPIIb-IIIa Complex,
pubmed-meshheading:16778135-Thrombosis,
pubmed-meshheading:16778135-Tyrosine
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| pubmed:year |
2006
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| pubmed:articleTitle |
Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets.
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| pubmed:affiliation |
Department of Cardiology, University of Freiburg, Freiburg, Germany. schwarz@med1.ukl.uni-freiburg.de
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| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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