Immunological Reviews 1992, No. 129 Published by Munksgaard, Copenhagen. Denmark No part tnay be reproduced by any process without written permission from the author(s)

Use of Monoclonal Antibodies in vivo as a Therapeutic Strategy for Alloimmune or Autoimmune Reactivity: The Besangon Experience p. HERVE', E . R A C A D O T ' , D . WENDLING^ L. RUMBACH^ P. TiBERGHIEN*, J. Y. CAHN^ M. FLESCH^ & J. WlJDENES'

INTRODUCTION Today, it is possible to obtain from mice or rats large quantities of monoclonal antibodies able to recognize a single antigenic determinant or epitope. These monoclonal antibodies (mAb) can be purified with appropriate separation techniques. mAb are a priori ideal itnmunosuppressive agents, since they have the ability to control the immune response to a defined target molecule without interfering with the response to other molecules (Waldmann 1989). Monoclonal antibody action involves several different mechanisms: either depletion, through a cytolysis of the T cells involved in the reaction (complementdependent or antibody-dependent cytolysis) or functional inhibition, by blocking molecules expressed on T cells (CD4, CD8), receptors involved in the allogeneic response (IL-2 receptor), adhesion molecules or their ligand, or cytokines (TNFa). The clinical efficacy of mAb-mediated immunosuppression is closely related to the mAb ability to trigger the natural host effector mechanisms, such as complement-dependent or Fc receptor-dependent cytolysis. Several factors, associated or not with the recruited effector mechanism, determine the efficacy of mAb on their targets; among these factors, the antibody isotype, the antigen density and the Fc receptor involved are the most important. We report our own experience in clinical pilot studies assessing the potential chnical efficacy of * Bone Marrow Transplantation Unit, Hopital Jean Minjoz, 'Centre Regional de Transfusion Sanguine, 'Service de Rhumatologie, Hopital Jean Minjoz, ^Service de Neurologic Hopital Jean Minjoz, Besan^on, France. Correspondence: Patrick Herve, MD, Centre Regional de Transfusion Sanguine, 1, Boulevard Fleming, 25020 Besan^on, France.

32

HERVE ET AL.

either anti-T lymphocyte or anti-cytokine monoclonal antibodies in the selective strategies for monoclonal antibody therapy either in two auto-immune diseases - rheumatoid arthritis and multiple sclerosis - or graft-versus-host disease after human allogeneic bone marrow transplantation. All the following studies received approval from the local Ethics Committee and informed consent was obtained from each patient.

ANTI-T MONOCLONAL ANTIBODIES Anti-IL2 receptor antibody in acute graft-versus-host disease Acute graft-versus-host disease (GvHD) remains a major complication in allogeneic bone marrow transplantation. Combinations of drugs {i.e., methotrexate plus cyclosporine or cyclosporine plus steroids) have reduced GvHD incidence to about 25% to 30% in transplants from HLA-identical related donors. On the other hand, current prophylactic protocols lead to 70 to 90% GvHD ^11 in patients grafted from a related mismatched or unrelated matched donor (HensleeDowney 1990, Herve et al. 1990a). Acute graft-versus-host disease has an ambivalent activity. When moderate, it has a beneficial effect in terms of relapse-free survival (graft-versus-leukemia effect), but, when severe, it becomes deleterious {Ferrara & Deeg 1991). Survival after an episode of acute GvHD depends on whether complete or partial response to corticotherapy is achieved. The incidence of mortality in severe forms of acute GvHD is extremely high, ranging from 50 to 90% of the cases, depending on the published series (Weisdorf et al. 1991, Martin et al. 1991). Experimental animal models have highlighted the primary role played by T lymphocytes in the genesis of acute GvHD {Korngold & Sprent 1987). Later, the role of IL-2 as a recruiting and proliferating agent of GvHD efTector cells was established {Smith 1988). Based on these pathophysiological concepts, techniques for the prevention of acute GvHD have been developed using total or selective T-cell depletion of the graft. Also, trials of in vivo therapy of acute GvHD with the use of monoclonal anti-T cell or anti-IL-2 receptor antibodies have been carried out in an attempt to control the effector cell population {Volk et al. 1986, Ferrara et al. 1986, Waldman 1988, 1989, Herve et al. 1990b). Yet, although T lymphocytes and IL-2 play a major role, other effector cells or cytokines also play important roles in GvHD. Among effector cytokines, TNFa, produced mainly by monocytes/macrophages and by T lymphocytes, is regarded as a major effector cytokine in GvHD {Piguet 1990). We now report the results of two phase MI studies assessing the clinical efficacy of two murine IgGl monoclonal antibodies: anti-IL-2R {termed B-BIO) administred to patients with acute GvHD refractory to corticosteroid treatment.

mAb FOR IMMUNE REACTIVITY TREATMENT

33

Patients and Methods In a multicenter study, 99 patients who experienced a steroid-resistant acute GvHD were entered into a clinical trial assessing the efficacy of the monoclonal anti-IL-2R antibody in the treatment of refractory acute GvHD. Among these patients, 69 underwent a bone marrow transplantation from HLA-identical siblings, 11 from partially-matched related donors and 19 from matched unrelated donors. GvHD was grade II in 56 patients. III in 32 patients and IV in 11 patients. The median delay from the onset of GvHD to B-BIO administration was 18 days {

Use of monoclonal antibodies in vivo as a therapeutic strategy for alloimmune or autoimmune reactivity: the Besançon experience.

Immunological Reviews 1992, No. 129 Published by Munksgaard, Copenhagen. Denmark No part tnay be reproduced by any process without written permission...
8MB Sizes 0 Downloads 0 Views