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Research Articles: Therapeutics, Targets, and Development

Targeted drug delivery to mesothelioma cells using functionally selected internalizing human single-chain antibodies

¹ Department of Anesthesia, ² Lung Biology Center, Department of Medicine, ³ Department of Pathology, ⁴ Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California and ⁵ Hermes Biosciences, South San Francisco, California

Requests for reprints: Bin Liu, Department of Anesthesia, University of California-San Francisco, 1001 Potrero Avenue, 3C38, San Francisco, CA 94110. Phone: 415-206-6973; Fax: 415-206-6276. E-mail: liub{at}anesthesia.ucsf.edu

Abstract

Mesothelioma is a malignancy of the mesothelium and current treatments are generally ineffective. One promising area of anticancer drug development is to explore tumor susceptibility to targeted therapy. To achieve efficient, targeted intracellular delivery of therapeutic agents to mesothelioma cells, we selected a naive human single-chain (scFv) phage antibody display library directly on the surface of live mesothelioma cells to identify internalizing antibodies that target mesothelioma-associated cell surface antigens. We have identified a panel of internalizing scFvs that bind to mesothelioma cell lines derived from both epithelioid (M28) and sarcomatous (VAMT-1) types of this disease. Most importantly, these antibodies stain mesothelioma cells in situ and therefore define a panel of clinically represented tumor antigens. We have further exploited the internalizing function of these scFvs to achieve targeted intracellular drug delivery to mesothelioma cells. We showed that scFv-targeted immunoliposomes were efficiently and specifically taken up by both epithelioid and sarcomatous mesothelioma cells, but not control cells, and immunoliposomes encapsulating the small-molecule drug topotecan caused targeted killing of both types of mesothelioma cells in vitro. [Mol Cancer Ther 2008;7(3):569–78]

Grant support: Mesothelioma Applied Research Foundation (B. Liu and V.C. Broaddus) and NIH grants R01 CA118919 (B. Liu) and CA95671 (V.C. Broaddus).

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.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/21/07; revised 11/ 4/07; accepted 11/29/07.