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Rituximab-CD20 Complexes Are Shaved from Z138 Mantle Cell Lymphoma Cells in Intravenous and Subcutaneous SCID Mouse Models¹

Yongli Li^*, Michael E. Williams, John B. Cousar, Andrew W. Pawluczkowycz^*, Margaret A. Lindorfer^* and Ronald P. Taylor^2,*

^* Department of Biochemistry and Molecular Genetics, Division of Hematology/Oncology and Hematologic Malignancy Program and Department of Medicine and Cancer Center, and Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908

Infusion of standard-dose rituximab (RTX) in chronic lymphocytic leukemia (CLL) patients promotes rapid complement activation and deposition of C3 fragments on CLL B cells. However, immediately after RTX infusions, there is substantial loss (shaving) of CD20 from circulating malignant cells. Because shaving can compromise efficacies of anticancer immunotherapeutic mAbs, we investigated whether shaving occurs in SCID mouse models. Z138 cells, a B cell line derived from human mantle cell lymphoma, were infused i.v. or s.c. The i.v. model recapitulates findings we previously reported for therapeutic RTX in CLL: i.v. infused RTX rapidly binds to Z138 cells in lungs, and binding is accompanied by deposition of C3 fragments. However, within 1 h targeted cells lose bound RTX and CD20, and these shaved cells are still demonstrable 40 h after RTX infusion. Z138 cells grow in tumors at s.c. injection sites, and infusion of large amounts of RTX (0.50 mg on each of 4 days) leads to considerable loss of CD20 from these cells. Human i.v. Ig blocked shaving, suggesting that FcRI on cells of the mononuclear phagocytic system promote shaving. Examination of frozen tumor sections from treated mice by immunofluorescence revealed large areas of B cells devoid of CD20, with CD20 intact in adjacent areas; it is likely that RTX had opsonized Z138 cells closest to capillaries, and these cells were shaved by monocyte/macrophages. The shaving reaction occurs in neoplastic B cells in tissue and in peripheral blood, and strategies to enhance therapeutic targeting and block shaving are under development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the Lymphoma Research Foundation Mantle Cell Lymphoma Grant (to M.E.W.) and the University of Virginia Cancer Support Grant.

² Address correspondence and reprint requests to Dr. Ronald P. Taylor, Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, P.O. Box 800733, Charlottesville, VA 22908-0733. E-mail address: rpt{at}virginia.edu

³ Abbreviations used in this paper: ADCC, antibody-dependent cellular cytotoxicity; Al, Alexa; bt, biotinylated; CLL, chronic lymphocytic leukemia; MESF, molecules of equivalent soluble fluorochrome; PI, propidium iodide; RTX, rituximab; CDC, complement-dependent cytotoxicity; IVIG, intravenous Ig.

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