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

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Abstract
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 p56lck. An uncoupling of p56lck 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]