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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2712-2719
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for
treatment of steroid-refractory acute graft-versus-host
disease
Paul A. Carpenter,
Frederick R. Appelbaum,
Lawrence Corey,
H. Joachim Deeg,
Kris Doney,
Theodore Gooley,
James Krueger,
Paul Martin,
Sandra Pavlovic,
Jean Sanders,
John Slattery,
Daniel Levitt,
Rainer Storb,
Ann Woolfrey, and
Claudio Anasetti
From the Division of Clinical Research, Fred Hutchinson
Cancer Research Center, and Departments of Pediatrics and Medicine,
Division of Oncology, University of Washington, Seattle;
Rockefeller University, Department of Investigative Dermatology, New
York, NY; and Protein Design Labs, Fremont, CA.
Visilizumab is a humanized anti-CD3 monoclonal antibody
characterized by a mutated IgG2 isotype, lack of binding to
Fc -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/m2) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m2 caused delayed
visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m2 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.
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