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A Human CD4 Monoclonal Antibody for the Treatment of T-Cell Lymphoma Combines Inhibition of T-Cell Signaling by a Dual Mechanism with Potent Fc-Dependent Effector Activity

¹ Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom; ² Genmab B.V.; ³ Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; ⁴ Genmab A/S, Copenhagen K, Denmark; and ⁵ Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Paul W.H.I. Parren, Genmab B.V., P. O. Box 85199, 3508 AD Utrecht, the Netherlands. Phone: 31-30-2123108; Fax: 31-30-2123196; E-mail: p.parren{at}genmab.com.

Zanolimumab is a human IgG1 antibody against CD4, which is in clinical development for the treatment of cutaneous and nodal T-cell lymphomas. Here, we report on its mechanisms of action. Zanolimumab was found to inhibit CD4⁺ T cells by combining signaling inhibition with the induction of Fc-dependent effector mechanisms. First, T-cell receptor (TCR) signal transduction is inhibited by zanolimumab through a fast, dual mechanism, which is activated within minutes. Ligation of CD4 by zanolimumab effectively inhibits early TCR signaling events but, interestingly, activates signaling through the CD4-associated tyrosine kinase p56^lck. An uncoupling of p56^lck from the TCR by anti-CD4 allows the kinase to transmit direct inhibitory signals via the inhibitory adaptor molecules Dok-1 and SHIP-1. Second, CD4⁺ T cells are killed by induction of antibody-dependent cell-mediated cytotoxicity, to which CD45RO⁺ cells are more sensitive than CD45RA⁺ cells. Finally, zanolimumab induces down-modulation of CD4 from cell surfaces via a slow Fc-dependent mechanism. In conclusion, zanolimumab rapidly inhibits T-cell signaling via a dual mechanism of action combined with potent Fc-dependent lysis of CD4⁺ T cells and may act long-term by down-regulating CD4. [Cancer Res 2007;67(20):9945–53]

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