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Targeting IFN-alpha to B cell lymphoma by a tumor-specific antibody elicits potent antitumor activities.

Abstract
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.
AuthorsTzu-Hsuan Huang, Koteswara R Chintalacharuvu, Sherie L Morrison
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 10 Pg. 6881-8 (Nov 15 2007) ISSN: 0022-1767 [Print] United States
PMID17982079 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Immunoglobulin G
  • Interferon-alpha
  • Recombinant Fusion Proteins
  • ERBB2 protein, human
  • Receptor, ErbB-2
Topics
  • Animals
  • Antineoplastic Agents (immunology, pharmacology)
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems
  • Drug Screening Assays, Antitumor
  • Half-Life
  • Humans
  • Immunity, Innate (drug effects)
  • Immunoglobulin G (immunology, pharmacology)
  • Interferon-alpha (immunology, pharmacology)
  • Lymphoma, B-Cell (drug therapy, immunology)
  • Mice
  • Neoplasms, Experimental (drug therapy, immunology)
  • Receptor, ErbB-2 (immunology)
  • Recombinant Fusion Proteins (immunology, pharmacology)

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