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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2004-8-9
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pubmed:abstractText |
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Follistatin,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/TMEFF2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/soblidotin
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1535-7163
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pubmed:author |
pubmed-author:AfarDaniel E HDE,
pubmed-author:AndersonTerriT,
pubmed-author:BhaskarVinayV,
pubmed-author:BreinbergDannaD,
pubmed-author:CarasIngridI,
pubmed-author:Cordon-CardoCarlosC,
pubmed-author:DrobnjakMarijaM,
pubmed-author:DuBridgeRobert BRB,
pubmed-author:EvangelistaFerdinandF,
pubmed-author:GrygielJohn JJJ,
pubmed-author:HenshallSusan MSM,
pubmed-author:IbsenEricE,
pubmed-author:KenchJames GJG,
pubmed-author:LawDebbie ADA,
pubmed-author:MurrayRichardR,
pubmed-author:O'HaraChrisC,
pubmed-author:PowersDavidD,
pubmed-author:PowersRickR,
pubmed-author:RamakrishnanVanithaV,
pubmed-author:ScherHoward IHI,
pubmed-author:SolvasonNanetteN,
pubmed-author:StrickerPhillip DPD,
pubmed-author:SutherlandRobert LRL,
pubmed-author:WinterRuthR,
pubmed-author:WongMelanieM
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pubmed:issnType |
Print
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pubmed:volume |
3
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
921-32
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:15299075-Amino Acid Sequence,
pubmed-meshheading:15299075-Animals,
pubmed-meshheading:15299075-Antibodies, Monoclonal,
pubmed-meshheading:15299075-Antineoplastic Agents,
pubmed-meshheading:15299075-Brain,
pubmed-meshheading:15299075-Cell Membrane,
pubmed-meshheading:15299075-Cell Proliferation,
pubmed-meshheading:15299075-Cloning, Molecular,
pubmed-meshheading:15299075-DNA, Complementary,
pubmed-meshheading:15299075-Flow Cytometry,
pubmed-meshheading:15299075-Follistatin,
pubmed-meshheading:15299075-Humans,
pubmed-meshheading:15299075-Hybridomas,
pubmed-meshheading:15299075-Immunohistochemistry,
pubmed-meshheading:15299075-Kinetics,
pubmed-meshheading:15299075-Lymphatic Metastasis,
pubmed-meshheading:15299075-Male,
pubmed-meshheading:15299075-Membrane Proteins,
pubmed-meshheading:15299075-Mice,
pubmed-meshheading:15299075-Microscopy, Fluorescence,
pubmed-meshheading:15299075-Molecular Sequence Data,
pubmed-meshheading:15299075-Neoplasm Metastasis,
pubmed-meshheading:15299075-Neoplasm Proteins,
pubmed-meshheading:15299075-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:15299075-Oligopeptides,
pubmed-meshheading:15299075-Prostate,
pubmed-meshheading:15299075-Prostatic Neoplasms,
pubmed-meshheading:15299075-Protein Structure, Tertiary,
pubmed-meshheading:15299075-RNA, Messenger,
pubmed-meshheading:15299075-Recombinant Fusion Proteins,
pubmed-meshheading:15299075-Sequence Homology, Amino Acid,
pubmed-meshheading:15299075-Surface Plasmon Resonance,
pubmed-meshheading:15299075-Time Factors,
pubmed-meshheading:15299075-Transfection
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pubmed:year |
2004
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pubmed:articleTitle |
Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer.
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pubmed:affiliation |
Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555, USA. dafar@pdl.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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