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

Cancer Res. 2007 Oct 15;67(20):9945-53. doi: 10.1158/0008-5472.CAN-07-1148.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity
  • CD3 Complex / immunology
  • CD4 Antigens / biosynthesis
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / 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*
  • Lymphoma, T-Cell, Cutaneous / therapy*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Psoriasis / immunology
  • Psoriasis / therapy
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects

Substances

  • 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