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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.
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NEOPLASIA
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
From the Divisions of Clinical Research and Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Departments of Pathology and Pediatrics, University of Washington, Seattle.
Gemtuzumab ozogamicin (GO; Mylotarg), 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.
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