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Binding of Rituximab, Trastuzumab, Cetuximab, or mAb T101 to Cancer Cells Promotes Trogocytosis Mediated by THP-1 Cells and Monocytes¹

Paul V. Beum^*, David A. Mack, Andrew W. Pawluczkowycz^*, Margaret A. Lindorfer^* and Ronald P. Taylor^2,*

^* Department of Biochemistry and Molecular Genetics and Hematology/Oncology Division, University of Virginia School of Medicine, Charlottesville, VA 22908

More than 20 years ago clinical investigations in the immunotherapy of cancer revealed that infusion of certain immunotherapeutic mAbs directed to tumor cells induced loss of targeted epitopes. This phenomenon, called antigenic modulation, can compromise mAb-based therapies. Recently we reported that rituximab (RTX) treatment of chronic lymphocytic leukemia patients induced substantial loss of targeted CD20 on B cells found in the circulation after RTX infusion; this "shaving" of RTX-CD20 complexes from B cells is also promoted in vitro by THP-1 monocytes and by PBMC in a reaction mediated by Fc receptors. The mechanism responsible for shaving appears to be trogocytosis, a process in which receptors on effector cells remove and internalize cognate ligands and cell membrane fragments from target cells. We now report that three therapeutic mAbs approved by the U.S. Food and Drug Administration for the treatment of cancer, RTX, cetuximab, and trastuzumab, as well as mAb T101, which has been shown to induce antigenic modulation in the clinic, promote trogocytosis in vitro upon binding to their respective target cells. Trogocytosis of the mAb-opsonized cells is mediated by THP-1 monocytes and by primary monocytes isolated from PBMC. In view of these results, it is likely that these mAbs and possibly other anticancer mAbs now used in the clinic may promote trogocytic removal of the therapeutic mAbs and their cognate Ags from tumor cells in vivo. Our findings may have important implications with respect to the use of mAbs in cancer immunotherapy.

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 research was supported through a grant to the University of Virginia Cancer Center from the James and Rebecca Craig Foundation, by a grant from CLL (Chronic Lymphocytic Leukemia) Topics, and by the University of Virginia Cancer Center Support Grant.

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

³ Abbreviations used in this paper: RTX, rituximab; Al, Alexa; bt, biotinylated; CET, cetuximab; CLL, chronic lymphocytic leukemia; Gt, goat; IC, immune complex(es); MESF, molecules of equivalent soluble fluorochome; Ms, mouse; RA, retinoic acid; SA, streptavidin; TRA, trastuzumab.

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