title: Regulation of T cell response by blocking the ICOS signal with the B7RP-1-specific small antibody fragment isolated from human antibody phage library.
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).
authors.affiliation: Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Kagoshima, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Maeda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ito
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hatanaka
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Torikai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakashima
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sugimura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008969:Molecular Sequence Data; D019151:Peptide Library; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007128:Immunoglobulin Fragments; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D019151:Peptide Library