| Direct targeting of alphavbeta3 integrin on tumor cells with a monoclonal antibody, Abegrin. | |
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MedLine Citation:
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PMID: 17172415 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The humanized monoclonal antibody Abegrin, currently in phase II trials for treatment of solid tumors, specifically recognizes the integrin alphavbeta3. Due to its high expression on mature osteoclasts, angiogenic endothelial cells, and tumor cells, integrin alphavbeta3 functions in several pathologic processes important to tumor growth and metastasis. Targeting of this integrin with Abegrin results in antitumor, antiangiogenic, and antiosteolytic activities. Here, we exploit the species specificity of Abegrin to evaluate the effects of direct targeting of tumor cells (independent of targeting of endothelia or osteoclasts). Flow cytometry analysis of human tumor cell lines shows high levels of alphavbeta3 on many solid tumors, including cancers of the prostate, skin, ovary, kidney, lung, and breast. We also show that tumor growth of alphavbeta3-expressing tumor cells is inhibited by Abegrin in a dose-dependent manner. We present a novel finding that high-dose administration can actively impair the antitumor activity of Abegrin. We also provide evidence that antibody-dependent cellular cytotoxicity contributes to in vitro and in vivo antitumor activity. Finally, it was observed that peak biological activity of Abegrin arises at serum levels that are consistent with those achieved in clinical trials. These results support a concept that Abegrin can be used to achieve selective targeting of the many tumor cells that express alphavbeta3 integrin. In combination with the well-established concept that alphavbeta3 plays a key role in cancer-associated angiogenesis and osteolytic activities, this triad of activity could provide new opportunities for therapeutic targeting of cancer. |
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Authors:
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Kathy Mulgrew; Krista Kinneer; Xiao-Tao Yao; Beth K Ward; Melissa M Damschroder; Bill Walsh; Su-Yau Mao; Changshou Gao; Peter A Kiener; Steve Coats; Michael S Kinch; David A Tice |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 5 ISSN: 1535-7163 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2006-12-18 Completed Date: 2007-06-07 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 3122-9 Citation Subset: IM |
Affiliation:
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MedImmune, Inc., One Medimmune Way, Gaithersburg, MD 20878, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / immunology, pharmacology* Antibody-Dependent Cell Cytotoxicity Cell Line, Tumor Dose-Response Relationship, Immunologic Female Humans Integrin alphaVbeta3 / biosynthesis, immunology* Mice Mice, Nude Mice, SCID Neoplasms / immunology, therapy* Species Specificity Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Integrin alphaVbeta3; 303127-73-3/etaracizumab |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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