A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease.
Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.
Carpenter
Paul A
PA
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, USA. pcarpent@fhcrc.org
Appelbaum
Frederick R
FR
Corey
Lawrence
L
Deeg
H Joachim
HJ
Doney
Kris
K
Gooley
Theodore
T
Krueger
James
J
Martin
Paul
P
Pavlovic
Sandra
S
Sanders
Jean
J
Slattery
John
J
Levitt
Daniel
D
Storb
Rainer
R
Woolfrey
Ann
A
Anasetti
Claudio
C
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000401:mortality; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014775:Virus Activation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; C115335:CD3E protein, human; D005938:Glucocorticoids; D011948:Receptors, Antigen, T-Cell; C456519:visilizumab