Targeting IFN-alpha to B cell lymphoma by a tumor-specific antibody elicits potent antitumor activities.
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.
Huang
Tzu-Hsuan
TH
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
Chintalacharuvu
Koteswara R
KR
Morrison
Sherie L
SL
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D016898:Interferon-alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human