Source:http://linkedlifedata.com/resource/pubmed/id/18656482
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
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| pubmed:dateCreated |
2008-9-1
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| pubmed:abstractText |
The alpha v beta 6 integrin is a promising target for cancer therapy. Its expression is up-regulated de novo on many types of carcinoma where it may activate transforming growth factor-beta1 and transforming growth factor-beta 3, interact with the specific extracellular matrix proteins and promote migration and invasion of tumor cells. The viral protein 1 (VP1) coat protein of the O(1) British field strain serotype of foot-and-mouth disease virus is a high-affinity ligand for alpha v beta 6, and we recently reported that a peptide derived from VP1 exhibited alpha v beta 6-specific binding in vitro and in vivo. We hypothesized that this peptide could confer binding specificity of an antibody to alpha v beta 6. A 17-mer peptide of VP1 was inserted into the complementarity-determining region H3 loop of MFE-23, a murine single-chain Fv (scFv) antibody reactive with carcinoembryonic antigen (CEA). The resultant scFv (B6-1) bound to alpha v beta 6 but retained residual reactivity with CEA. This was eliminated by point mutation (Y100bP) in the variable heavy-chain domain to create an scFv (B6-2) that was as structurally stable as MFE-23 and reacted specifically with alpha v beta 6 but not with alpha 5 beta 1, alpha v beta 3, alpha v beta 5, alpha v beta 8 or CEA. B6-2 was internalized into alpha v beta 6-expressing cells and inhibited alpha v beta 6-dependent migration of carcinoma cells. B6-2 was subsequently humanized. The humanized form (B6-3) was obtained as a non-covalent dimer from secretion in Pichia pastoris (115 mg/l) and was a potent inhibitor of alpha v beta 6-mediated cell adhesion. Thus, we have used a rational stepwise approach to create a humanized scFv with therapeutic potential to block alpha v beta 6-mediated cancer cell invasion or to deliver and internalize toxins specifically to alpha v beta 6-expressing tumors.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Capsid Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Carcinoembryonic Antigen,
http://linkedlifedata.com/resource/pubmed/chemical/Complementarity Determining Regions,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin Variable Region,
http://linkedlifedata.com/resource/pubmed/chemical/Integrins,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/VP1 protein, Foot-and-mouth...,
http://linkedlifedata.com/resource/pubmed/chemical/arginyl-glycyl-aspartic acid,
http://linkedlifedata.com/resource/pubmed/chemical/integrin alphavbeta6
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| pubmed:status |
MEDLINE
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| pubmed:month |
Oct
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| pubmed:issn |
1089-8638
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| pubmed:author |
pubmed-author:BegentRichard H JRH,
pubmed-author:ChesterKerryK,
pubmed-author:Di CaraDanielleD,
pubmed-author:HartIanI,
pubmed-author:KogelbergHeideH,
pubmed-author:LowdellMark WMW,
pubmed-author:MarshDanD,
pubmed-author:MarshallJohn FJF,
pubmed-author:MeyerTimT,
pubmed-author:MinogueShaneS,
pubmed-author:RameshBalaB,
pubmed-author:SodhaSerenaS,
pubmed-author:ThomasGareth JGJ,
pubmed-author:TolnerBerendB
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| pubmed:issnType |
Electronic
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| pubmed:day |
3
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| pubmed:volume |
382
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
385-401
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| pubmed:dateRevised |
2010-12-3
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| pubmed:meshHeading |
pubmed-meshheading:18656482-Amino Acid Sequence,
pubmed-meshheading:18656482-Animals,
pubmed-meshheading:18656482-Antigens, Neoplasm,
pubmed-meshheading:18656482-Capsid Proteins,
pubmed-meshheading:18656482-Carcinoembryonic Antigen,
pubmed-meshheading:18656482-Cell Line,
pubmed-meshheading:18656482-Cell Movement,
pubmed-meshheading:18656482-Complementarity Determining Regions,
pubmed-meshheading:18656482-Foot-and-Mouth Disease Virus,
pubmed-meshheading:18656482-Humans,
pubmed-meshheading:18656482-Immunoglobulin Fragments,
pubmed-meshheading:18656482-Immunoglobulin Variable Region,
pubmed-meshheading:18656482-Integrins,
pubmed-meshheading:18656482-Mice,
pubmed-meshheading:18656482-Models, Molecular,
pubmed-meshheading:18656482-Molecular Sequence Data,
pubmed-meshheading:18656482-Oligopeptides,
pubmed-meshheading:18656482-Protein Conformation,
pubmed-meshheading:18656482-Protein Engineering
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| pubmed:year |
2008
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| pubmed:articleTitle |
Engineering a single-chain Fv antibody to alpha v beta 6 integrin using the specificity-determining loop of a foot-and-mouth disease virus.
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| pubmed:affiliation |
Cancer Research UK Targeting and Imaging Group, Department of Oncology, Royal Free & University College Medical School, Hampstead Campus, London NW3 2PF, UK. h.kogelberg@ucl.ac.uk
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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