title: Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor.
abstract: Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL-2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center 98104.
authors.forename: C
authors.initials: C
authors.lastname: Anasetti
authors.forename: J A
authors.initials: JA
authors.lastname: Hansen
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
authors.forename: K
authors.initials: K
authors.lastname: Doney
authors.forename: P J
authors.initials: PJ
authors.lastname: Martin
authors.forename: R
authors.initials: R
authors.lastname: Nash
authors.forename: R
authors.initials: R
authors.lastname: Storb
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000145:classification / Q000627:therapeutic use*; D007938:Leukemia / Q000628:therapy; D008214:Lymphocytes / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000628:therapy; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D046911:Macromolecular Substances; D015375:Receptors, Interleukin-2