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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4308-4314. Prepublished online as a Blood First Edition Paper on August 18, 2005; DOI 10.1182/blood-2005-03-1033. This Article Full Text (PDF) All Versions of this Article: 2005-03-1033v1 106/13/4308    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chang, C.-H. Articles by Goldenberg, D. M Search for Related Content PubMed PubMed Citation Articles by Chang, C.-H. Articles by Goldenberg, D. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 14, 2005 Accepted August 11, 2005 Effective therapy of human lymphoma xenografts with a novel recombinant ribonuclease/anti-CD74 humanized IgG4 antibody immunotoxin Chien-Hsing Chang, Puja Sapra, Sailaja S Vanama, Hans J Hansen, Ivan D Horak, and David M Goldenberg* Immunomedics, Inc., Morris Plains, NJ, USA Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA * Corresponding author; email: dmg.gscancer{at}att.net. Ranpirnase (Rap) is a cytotoxic ribonuclease (RNase) isolated from frog oocytes. Here we describe high antitumor activity of a novel immunotoxin, 2L-Rap-hLL1-4P, composed of two Rap molecules, each fused to the N-terminus of the light chain of hLL1, an internalizing anti-CD74 humanized antibody. To reduce unwanted side effects, the constant region of hLL1 was changed from 1 to -4 and further to 4P by replacing serine228 to proline to prevent the formation of a half-IgG common for IgG4. In vitro, 2L-Rap-hLL1-4P retained RNase activity, specific binding to CD74,- and was significantly more potent against CD74-positive cell lines (Daudi, Raji and MC/CAR) than naked hLL1. In vivo, the pharmacokinetic profile of 2L-Rap-hLL1-4P was similar to that of naked hLL1. The maximum tolerated dose of 2L-Rap-hLL1-4P in SCID or BALB/c mice was 50 µg/mouse. In Raji and Daudi Burkitt's lymphoma xenograft models, treatment with a single 5- to 50-µg dose of 2L-Rap-hLL1-4P, given as early or delayed treatment, resulted in cures of most animals. Treatment with 2L-Rap-hLL1-4P was significantly better than all controls, including saline, naked hLL1 and non-specific immunotoxin. In conclusion, 2L-Rap-hLL1-4P demonstrated excellent in vitro and in vivo efficacy, and thus merits further consideration as a therapeutic for CD74-positive tumors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Stein, M. J. Mattes, T. M. Cardillo, H. J. Hansen, C.-H. Chang, J. Burton, S. Govindan, and D. M. Goldenberg CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms Clin. Cancer Res., September 15, 2007; 13(18): 5556s - 5563s. [Abstract] [Full Text] [PDF] R. M. Sharkey and D. M. Goldenberg Targeted Therapy of Cancer: New Prospects for Antibodies and Immunoconjugates CA Cancer J Clin, July 1, 2006; 56(4): 226 - 243. [Abstract] [Full Text] [PDF]

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