Regulation of T cell response by blocking the ICOS signal with the B7RP-1-specific small antibody fragment isolated from human antibody phage library

MAbs. 2009 Sep-Oct;1(5):453-61. doi: 10.4161/mabs.1.5.9633. Epub 2009 Sep 26.

Abstract

A costimulatory signal is required for the full activation of T cells, in addition to the antigen-specific signal via the T cell receptor. The inducible costimulator, ICOS is one of the costimulatory molecules that play an essential role in this process, particularly in the expansion or the development of effector T cells. As blocking of the interaction between ICOS and its ligand, B7RP-1, suppresses the T cell response, it can be applied to the treatment of allograft rejection or autoimmune diseases. Here, we isolated four scFv clones that were specific to human B7RP-1 by biopanning a human antibody phage library. We found that three of these clones inhibited the interaction between ICOS-Fc and B7RP-1-Fc. These inhibitory clones not only recognized B7RP-1 molecules expressed on B cells, as assessed by FACS, but also exhibited inhibitory activity in a proliferation assay of T cells stimulated with anti-CD3 mAb and B7RP-1-Fc. Finally, the suppression effect of the scFv on the allogenic immune response was examined using a mixed lymphocyte reaction assay, which demonstrated a successful inhibition of the allogenic reaction, in spite of the high dose needed for complete inhibition (360 nM).

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibody Specificity
  • Antigens, Differentiation, T-Lymphocyte / drug effects*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B7-1 Antigen / immunology*
  • Flow Cytometry
  • Humans
  • Immunoglobulin Fragments / chemistry
  • Immunoglobulin Fragments / immunology*
  • Immunoglobulin Fragments / therapeutic use
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Lymphocyte Activation* / drug effects
  • Lymphocyte Activation* / immunology
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Molecular Sequence Data
  • Peptide Library
  • Surface Plasmon Resonance
  • T-Lymphocytes* / drug effects
  • T-Lymphocytes* / immunology
  • Transplantation, Homologous / immunology

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • B7-1 Antigen
  • ICOS protein, human
  • Icos protein, mouse
  • Immunoglobulin Fragments
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Peptide Library