Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

Blood. 2013 Jan 17;121(3):556-65. doi: 10.1182/blood-2012-04-423392. Epub 2012 Nov 30.


Graft-versus-host disease (GVHD) induced by transplant-derived T cells represents a major complication after allogeneic bone marrow transplantation (BMT). However, these T cells support engraftment, early T-cell immunity, and mediate the graft-versus-tumor (GVT) effect. Cytotoxic effector functions by transplanted T cells are predominantly mediated by the perforin/granzyme and the CD95/CD95L system. APG101, a novel recombinant human fusion protein consisting of the extracellular domain of CD95 and the Fc domain of an IgG1 antibody inhibited CD95L-induced apoptosis without interfering with T-cell function in vitro and was therefore tested for its ability to prevent GVHD in murine BMT models across minor or major histocompatibility barriers. Starting APG101 treatment either 1 day before or 6 days after transplantation effectively reduced clinical GVHD and rescued survival between 60% and 100% if GVHD was CD95L mediated. APG101 did not interfere with the GVT effect, because P815 mastocytoma and most importantly primary Bcr-Abl-transformed B-cell leukemias were completely eradicated by the alloantigen-specific T cells. Phenotype and homing of alloantigen-specific T cells or their perforin/granzyme-mediated cytotoxicity and proliferative capacity were not affected by APG101 treatment suggesting that APG101 therapy might be useful in GVHD prophylaxis without impairing T-cell function and most importantly preserving GVT activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Bone Marrow Transplantation / adverse effects*
  • Bone Marrow Transplantation / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Disease Models, Animal
  • Female
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control*
  • Immunoglobulin G / immunology
  • Immunoglobulin G / pharmacology*
  • Immunophenotyping
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Neoplasms / immunology
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology*
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transplantation, Homologous
  • fas Receptor / immunology
  • fas Receptor / pharmacology*


  • Immunoglobulin G
  • Recombinant Fusion Proteins
  • fas Receptor
  • APG101