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Targeting IFN- to B Cell Lymphoma by a Tumor-Specific Antibody Elicits Potent Antitumor Activities¹

Tzu-Hsuan Huang^2,*, Koteswara R. Chintalacharuvu and Sherie L. Morrison

^* Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; and Department of Microbiology, Immunology and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, CA 90095

IFN-, a cytokine crucial for the innate immune response, also demonstrates antitumor activity. However, use of IFN- as an anticancer drug is hampered by its short half-life and toxicity. One approach to improving IFN-’s therapeutic index is to increase its half-life and tumor localization by fusing it to a tumor-specific Ab. In the present study, we constructed a fusion protein consisting of anti-HER2/neu-IgG3 and IFN- (anti-HER2/neu-IgG3-IFN-) and investigated its effect on a murine B cell lymphoma, 38C13, expressing human HER2/neu. Anti-HER2/neu-IgG3-IFN- exhibited potent inhibition of 38C13/HER2 tumor growth in vivo. Administration of three daily 1-µg doses of anti-HER2/neu-IgG3-IFN- beginning 1 day after tumor challenge resulted in 88% of the mice remaining tumor free. Remarkably, anti-HER2/neu-IgG3-IFN- demonstrated potent activity against established 38C13/HER2 tumors, with complete tumor remission observed in 38% of the mice treated with three daily doses of 5 µg of the fusion protein (p = 0.0001). Ab-mediated targeting of IFN- induced growth arrest and apoptosis of lymphoma cells contributing to the antitumor effect. The fusion protein also had a longer in vivo half-life than rIFN-. These results suggest that IFN- Ab fusion proteins may be effective in the treatment of B cell lymphoma.

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.

¹ This work was supported in part by Grant CA87990 from the National Institutes of Health. T.-H.H. was the recipient of a Dorothy Radcliffe Dee Fellowship.

² Address correspondence and reprint requests to Dr. Tzu-Hsuan Huang, Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, HSW 1002A, San Francisco, CA 94143-0534. E-mail address: lhuang{at}diabetes.ucsf.edu

³ Abbreviations used in this paper: TAA, tumor-associated Ag; DC, dendritic cell; GPS, glutamine/penicillin/streoptomycin; FPLC, fast protein liquid chromatography; VSV, vesicular stomatitis virus; MTS, mouse thymic stroma; PI, propidium iodide.