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Research Articles: Therapeutics, Targets, and Development

Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs

Departments of ¹ Advanced Therapeutics and ² Medical Oncology, British Columbia Cancer Research Center, ³ Department of Pathology and Laboratory Medicine, Faculty of Medicine, and ⁴ Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Gigi N.C. Chiu, Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4, 18 Science Drive 4, Singapore 117543, Singapore. Phone: 65-6516-5536; Fax: 65-6779-1554. E-mail: phacncg{at}nus.edu.sg

Abstract

Various methods have been explored to enhance antibody-based cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-B, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex. [Mol Cancer Ther 2007;6(3):844–55]

Grant support: Canadian Institutes of Health Research (M.B. Bally, G.N.C. Chiu, and D.N. Waterhouse), Canadian Breast Cancer Research Alliance (M.B. Bally), Lymphoma Foundation of America (R. Klasa), Academy of Finland, and Cultural Foundation of Finland (A.I. Kapanen).

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 3/23/06; revised 11/14/06; accepted 1/31/07.