Defining dose-response relationships in the therapeutic blockade of B7RP-1-dependent immune responses

Eur J Pharmacol. 2009 May 21;610(1-3):110-8. doi: 10.1016/j.ejphar.2009.03.023. Epub 2009 Mar 16.


The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.

MeSH terms

  • Aluminum Hydroxide / immunology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigen-Presenting Cells / immunology
  • Antigens, CD19 / metabolism
  • B-Lymphocytes / metabolism
  • B7-1 Antigen / genetics
  • B7-1 Antigen / pharmacology*
  • Binding Sites
  • CD3 Complex / metabolism
  • Cytokines / blood
  • Dose-Response Relationship, Drug
  • Female
  • Fluorescein-5-isothiocyanate / metabolism
  • Fluorescent Dyes / metabolism
  • Hemocyanins / immunology
  • Immune System Phenomena / drug effects*
  • Inducible T-Cell Co-Stimulator Ligand
  • Mice
  • Mice, Inbred BALB C
  • Models, Immunological
  • Protein Binding
  • Recombinant Fusion Proteins / pharmacology
  • T-Lymphocytes / metabolism
  • Temperature
  • Time Factors


  • Antibodies, Monoclonal
  • Antigens, CD19
  • B7-1 Antigen
  • CD3 Complex
  • Cytokines
  • Fluorescent Dyes
  • Inducible T-Cell Co-Stimulator Ligand
  • Recombinant Fusion Proteins
  • Aluminum Hydroxide
  • Hemocyanins
  • keyhole-limpet hemocyanin
  • Fluorescein-5-isothiocyanate