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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1295-1302. Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-07-2784. This Article Full Text (PDF) All Versions of this Article: 2004-07-2784v1 105/3/1295    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 Walter, R. B Articles by Bernstein, I. D Search for Related Content PubMed PubMed Citation Articles by Walter, R. B Articles by Bernstein, I. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 20, 2004 Accepted September 21, 2004 Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity Roland B Walter*, Brian W Raden, Darren M Kamikura, Jonathan A Cooper, and Irwin D Bernstein Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA * Corresponding author; email: rwalter{at}fhcrc.org. Gemtuzumab ozogamicin (GO; MylotargTM), a novel immunoconjugate used for treatment of acute myeloid leukemia (AML), contains the humanized anti-CD33 antibody (hP67.6) as a carrier to facilitate cellular uptake of the toxic calicheamicin-1 derivative. By use of lentivirus-mediated gene transfer to manipulate CD33 expression in myeloid cell lines that normally lack CD33 (murine 32D cells) or have very low levels of CD33 (human OCI-AML3 and KG-1a cells), we here show a quantitative relationship between CD33 expression and GO-induced cytotoxicity. The CD33 cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) control internalization of antibody bound to CD33. Disruption of the ITIMs by introduction of point mutations not only prevented effective internalization of antibody-bound CD33, but also significantly reduced GO-induced cytotoxicity. Together, our data imply a pivotal role of both the number of CD33 molecules expressed on the cell surface and the amount of internalization of CD33 following antibody binding for GO-induced cytotoxicity, and suggest novel therapeutic approaches for improvement of clinical outcome of patients treated with GO. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. B. Walter, K. M. Boyle, F. R. Appelbaum, I. D. Bernstein, and J. M. Pagel Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts Blood, May 1, 2008; 111(9): 4813 - 4816. [Abstract] [Full Text] [PDF] R. B. Walter, B. W. Raden, R. Zeng, P. Hausermann, I. D. Bernstein, and J. A. Cooper ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2 J. Leukoc. Biol., January 1, 2008; 83(1): 200 - 211. [Abstract] [Full Text] [PDF] M. Breccia, G. Cimino, D. Diverio, F. Gentilini, F. Mandelli, and F. L. Coco Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia Haematologica, September 1, 2007; 92(9): 1273 - 1274. [Abstract] [Full Text] [PDF] H. Tateno, H. Li, M. J. Schur, N. Bovin, P. R. Crocker, W. W. Wakarchuk, and J. C. Paulson Distinct Endocytic Mechanisms of CD22 (Siglec-2) and Siglec-F Reflect Roles in Cell Signaling and Innate Immunity Mol. Cell. Biol., August 15, 2007; 27(16): 5699 - 5710. [Abstract] [Full Text] [PDF] R. B. Walter, T. A. Gooley, V. H. J. van der Velden, M. R. Loken, J. J. M. van Dongen, D. A. Flowers, I. D. Bernstein, and F. R. Appelbaum CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy Blood, May 15, 2007; 109(10): 4168 - 4170. [Abstract] [Full Text] [PDF] C. Delaney, B. Varnum-Finney, K. Aoyama, C. Brashem-Stein, and I. D. Bernstein Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells Blood, October 15, 2005; 106(8): 2693 - 2699. [Abstract] [Full Text] [PDF] E. J. Feldman, J. Brandwein, R. Stone, M. Kalaycio, J. Moore, J. O'Connor, N. Wedel, G. J. Roboz, C. Miller, R. Chopra, et al. Phase III Randomized Multicenter Study of a Humanized Anti-CD33 Monoclonal Antibody, Lintuzumab, in Combination With Chemotherapy, Versus Chemotherapy Alone in Patients With Refractory or First-Relapsed Acute Myeloid Leukemia J. Clin. Oncol., June 20, 2005; 23(18): 4110 - 4116. 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