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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Ronald P. Taylor and Margaret A. Lindorfer
Molecular Pharmacology November 2014, 86 (5) 485-491; DOI: https://doi.org/10.1124/mol.114.092684
Ronald P. Taylor
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia
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Margaret A. Lindorfer
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia
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Abstract

Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body’s cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration–approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcγ receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30–50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.

Footnotes

    • Received March 12, 2014.
    • Accepted June 18, 2014.
  • The research was supported by the Commonwealth Foundation for Cancer Research, the National Institutes of Health National Cancer Institute [Grant P30-CA044579], Genmab, and GlaxoSmithKline.

  • dx.doi.org/10.1124/mol.114.092684.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Optimizing Doses for Monoclonal Antibodies in Cancer

Ronald P. Taylor and Margaret A. Lindorfer
Molecular Pharmacology November 1, 2014, 86 (5) 485-491; DOI: https://doi.org/10.1124/mol.114.092684

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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Optimizing Doses for Monoclonal Antibodies in Cancer

Ronald P. Taylor and Margaret A. Lindorfer
Molecular Pharmacology November 1, 2014, 86 (5) 485-491; DOI: https://doi.org/10.1124/mol.114.092684
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  • Article
    • Abstract
    • Introduction
    • Correlative Studies Associated with CD20 mAb Treatment of CLL
    • Trogocytosis of mAb-Opsonized Cells
    • The Importance of Exhaustion
    • Possible Generalization to Other Immunotherapeutic mAbs
    • Quantitative Considerations
    • Concluding Remarks: The Way Forward
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