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 Daniels, T. R. Articles by Penichet, M. L. Search for Related Content PubMed PubMed Citation Articles by Daniels, T. R. Articles by Penichet, M. L.

Research Articles: Therapeutics, Targets, and Development

Conjugation of an anti–transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells

¹ Division of Surgical Oncology, Department of Surgery; ² Division of Hematology and Oncology, Department of Medicine; ³ Jonsson Comprehensive Cancer Center; and ⁴ Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, California and ⁵ Department of Medicine, Oncology Division, Stanford University Medical Center, Stanford, California

Requests for reprints: Manuel L. Penichet, Division of Surgical Oncology, Department of Surgery, University of California at Los Angeles, 10833 Le Conte Avenue, CHS 54-140, Box 951782, Los Angeles, CA 90095-1782. Phone: 310-825-1304; Fax: 310-825-7575. E-mail: penichet{at}microbio.ucla.edu

Abstract

We have previously developed an antibody fusion protein composed of a mouse/human chimeric IgG3 specific for the human transferrin receptor genetically fused to avidin (anti-hTfR IgG3-Av) as a universal delivery system for cancer therapy. This fusion protein efficiently delivers biotinylated FITC into cancer cells via TfR-mediated endocytosis. In addition, anti-hTfR IgG3-Av alone exhibits intrinsic cytotoxic activity and interferes with hTfR recycling, leading to the rapid degradation of the TfR and lethal iron deprivation in certain malignant B-cell lines. We now report on the cytotoxic effects of a conjugate composed of anti-hTfR IgG3-Av and biotinylated saporin 6 (b-SO6), a toxin derived from the plant Saponaria officinalis that inhibits protein synthesis. Conjugation of anti-hTfR IgG3-Av with b-SO6 enhances the cytotoxic effect of the fusion protein in sensitive cells and also overcomes the resistance of malignant cells that show low sensitivity to the fusion protein alone. Our results show for the first time that loading anti-hTfR IgG3-Av with a biotinylated toxin enhances the cytotoxicity of the fusion protein alone. These results suggest that anti-hTfR IgG3-Av has great potential as a therapeutic agent for a wide range of applications due to its intrinsic cytotoxic activity plus its ability to deliver biotinylated molecules into cancer cells. [Mol Cancer Ther 2007;6(11):2995–3008]

Grant support: NIH/National Cancer Institute grants CA86915 and CA107023, NIH/National Cancer Institute research supplement CA107023-02S1, and the 2004 Brian D. Novis International Myeloma Foundation Senior Grant Award. The Minority Access to Research Careers, Center for Academic and Research Excellence, and Summer Programs in Undergraduate Research programs at University of California at Los Angeles provided generous support and funding.

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.

Note: T.R. Daniels and P.P. Ng contributed equally to this work.

⁶ Rodriguez et al., J Controlled Release, in press.

⁷ Unpublished results.

Received 5/14/07; revised 9/12/07; accepted 9/24/07.