Alefacept (AMEVIVE®) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH2, and CH3 domains) portion of human IgG1. Alefacept is produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) mammalian cell expression system. It was shown to interfere with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction. Alefacept was also shown to induce reduction in subsets of CD2+ T lymphocytes (primarily CD45RO+), presumably by bridging between CD2 on target lymphocytes and immunoglobulin Fc receptors on cytotoxic cells, such as natural killer cells. Treatment with alefacept of monkeys with cardiac allografts was shown to prolong allograft survival. It was also shown that alefacept treatment results in a reduction in circulating total CD4+ and CD8+ T lymphocyte counts. CD2 is also expressed at low levels on the surface of natural killer cells and certain bone marrow B-lymphocytes. Alefacept was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic ( > 1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic therapy or phototherapy. Each course consisted of once-weekly administration for 12 weeks (intravenous (IV) for Study 1, IM (intramuscular) for Study 2) of placebo or alefacept. The response to alefacept was significantly better in both studies. In both studies, onset of response to alefacept treatment (defined as at least 50% reduction of baseline Psoriasis Area and Severity Index (PASI)) began 60 days after the start of therapy. With one course of therapy in Study 1 (IV route), the median duration of response (defined as maintenance of a 75% or greater reduction in PASI) was 3.5 months for alefacept treated patients and 1 month for placebo-treated patients. In Study 2 (IM route), the median duration of response was approximately 2 months for both alefacept treated patients and placebo-treated patients. Most patients who had responded to either alefacept or placebo maintained a 50% or greater reduction in PASI through the 3-month observation period.

Graft versus host disease (GVHD) is the most ominous side effect of allogeneic stem cell transplantation (SCT). It causes severe inflammatory process, which is usually located to the skin, gut and liver. Treatment of GVHD consists of various immuno-suppressive and immuno-modulating drugs, including steroids, cyclosporine, tacrolimus, methotrexate etc. These drugs unfortunately can also cause severe immunologic failure that makes the patient prone to infection and malignancy, and other medication-specific side effects. In spite of this effect on the immune system, not all of the patients achieve control of GVHD, which usually rapidly leads to death. Despite the use of innovative immunosuppressive modalities, the prognosis of steroid resistant GVHD is usually poor.

It was shown that CD2 depletion of allografts could prevent GVHD. Alefacept was never systemically tried in GVHD but A phase II study of BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen in steroid-refractory acute GVHD showed a total response rate of 55%. The investigators showed that alefacept might have a beneficial effect in controlling steroid resistant GVHD.

The investigators therefore propose the following study.