Abstract
ABSTRACT: Immunotoxins are hybrid molecules consisting of a cell-specific compound, mostly onoclonal antibodies, conjugated to a potent bacterial or plant derived toxin, e.g. the A-chain of plant toxin ricin. By providing specific toxicity, immunotoxins form an attractive drug targeting concept with therapeutic potential for the treatment of a variety of malignancies and immunological disorders.The UMC St Radboud was among the first to introduce the immunotoxin research in the Netherlands, in 1983. This resulted in the first institutional clinical application, the ex vivo purging of autologous marrow grafts of patients suffering from T cell leukemia or lymphoma. Aim of this treatment was to reduce the incidence of a malignant relapse caused by residual malignant cells in the graft. At the mean time, the international excitement regarding the therapeutic possibilities of the 'magic- bullet concept' more or less drove the immunotoxins from the laboratory to the clinic. Several institutes, mostly US academic centers, initiated phase I/II studies based on the immunotoxin-targeting of diffuse and solid tumors and varying immune diseases. Encouraged by the outcome of these early studies, especially regarding the treatment of diffuse disorders, and motivated by the urgent clinical need, the Department of Hematology decided to develop an immunotoxin-based therapy for life-threatening Graft-versus-Host Disease (a major complication of allogeneic bone marrow transplantation).Chapter 1 of this thesis provides a general overview of the mechanisms of action and current status of immunotoxins. Chapter 2 focuses on the potential applications in the field of Hematology. The remaining chapters form a selection of the institutional immunotoxin-research during the last decade. They cover part of the early in vitro work (Chapter 3 to 5), and the set up and preliminary results of a clinical pilot study for the treatment of Graft-versus-Host Disease (Chapters 6 and 7).
