This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mulgrew, K. Articles by Tice, D. A. Search for Related Content PubMed PubMed Citation Articles by Mulgrew, K. Articles by Tice, D. A.

Research Articles: Therapeutics, Targets, and Development

Direct targeting of _vß₃ integrin on tumor cells with a monoclonal antibody, Abegrin^TM

MedImmune, Inc., Gaithersburg, Maryland

Requests for reprints: David A. Tice, MedImmune, Inc., One Medimmune Way, Gaithersburg, MD 20878. Phone: 301-398-4592; Fax: 301-398-9592. E-mail: ticed{at}medimmune.com

Abstract

The humanized monoclonal antibody Abegrin^TM, currently in phase II trials for treatment of solid tumors, specifically recognizes the integrin _vß₃. Due to its high expression on mature osteoclasts, angiogenic endothelial cells, and tumor cells, integrin _vß₃ functions in several pathologic processes important to tumor growth and metastasis. Targeting of this integrin with Abegrin^TM results in antitumor, antiangiogenic, and antiosteolytic activities. Here, we exploit the species specificity of Abegrin^TM 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 _vß₃ on many solid tumors, including cancers of the prostate, skin, ovary, kidney, lung, and breast. We also show that tumor growth of _vß₃-expressing tumor cells is inhibited by Abegrin^TM in a dose-dependent manner. We present a novel finding that high-dose administration can actively impair the antitumor activity of Abegrin^TM. 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^TM arises at serum levels that are consistent with those achieved in clinical trials. These results support a concept that Abegrin^TM can be used to achieve selective targeting of the many tumor cells that express _vß₃ integrin. In combination with the well-established concept that _vß₃ plays a key role in cancer-associated angiogenesis and osteolytic activities, this triad of activity could provide new opportunities for therapeutic targeting of cancer. [Mol Cancer Ther 2006;5(12):3122–9]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/21/06; revised 10/ 6/06; accepted 10/27/06.