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.

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.

• Authors: David A Rider, Carin E G Havenith, Ruby de Ridder, Janine Schuurman, Cedric Favre, Joanne C Cooper, Simon Walker, Ole Baadsgaard, Susanne Marschner, Jan G J vandeWinkel, John Cambier, Paul W H I Parren, Denis R Alexander
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 20 Pg. 9945-53 (Oct 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17942927 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CD3 Complex
• CD4 Antigens
• Receptors, Antigen, T-Cell
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
• Phosphoric Monoester Hydrolases
• Inositol Polyphosphate 5-Phosphatases
• INPP5D protein, human
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
• zanolimumab

Topics

• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibody-Dependent Cell Cytotoxicity
• CD3 Complex (immunology)
• CD4 Antigens (biosynthesis, genetics, immunology)
• CD4 Lymphocyte Count
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Double-Blind Method
• Down-Regulation
• Humans
• Inositol Polyphosphate 5-Phosphatases
• Lymphocyte Activation (drug effects)
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (metabolism)
• Lymphoma, T-Cell, Cutaneous (immunology, therapy)
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
• Phosphoric Monoester Hydrolases (metabolism)
• Phosphorylation
• Psoriasis (immunology, therapy)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Signal Transduction (drug effects)