IFN-alpha, a
cytokine crucial for the innate immune response, also demonstrates antitumor activity. However, use of IFN-alpha as an anticancer
drug is hampered by its short half-life and toxicity. One approach to improving IFN-alpha'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-alpha (anti-HER2/neu-
IgG3-IFN-alpha) and investigated its effect on a murine
B cell lymphoma, 38C13, expressing human HER2/neu. Anti-HER2/neu-
IgG3-IFN-alpha exhibited potent inhibition of 38C13/HER2
tumor growth in vivo. Administration of three daily 1-microg doses of anti-HER2/neu-
IgG3-IFN-alpha beginning 1 day after
tumor challenge resulted in 88% of the mice remaining
tumor free. Remarkably, anti-HER2/neu-
IgG3-IFN-alpha 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 microg of the fusion
protein (p = 0.0001). Ab-mediated targeting of IFN-alpha 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-alpha. These results suggest that IFN-alpha Ab fusion
proteins may be effective in the treatment of
B cell lymphoma.