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Alefacept

Mechanism of Action

Alefacept 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. The molecular weight of alefacept is 91.4 kilodaltons.

Alefacept interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction. Activation of T lymphocytes involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in the pathophysiology of chronic plaque psoriasis. The majority of T lymphocytes in psoriatic lesions are of the memory effector phenotype characterized by the presence of the CD45RO marker1, express activation markers (e.g., CD25, CD69) and release inflammatory cytokines, such as interferon γ.

Alefacept also causes a 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 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. Therefore, the potential exists for Alefacept to affect the activation and numbers of cells other than T lymphocytes. In clinical studies of alefacept, minor changes in the numbers of circulating cells other than T lymphocytes have been observed.

Pharmacodynamic Properties

At doses tested in clinical trials, alefacept therapy resulted in a dose-dependent decrease in circulating total lymphocytes. This reduction predominantly affected the memory effector subset of the CD4+ and CD8+ T lymphocyte compartments (CD4+CD45RO+ and CD8+CD45RO+), the predominant phenotype in psoriatic lesions. Circulating naïve T lymphocyte and natural killer cell counts appeared to be only minimally susceptible to alefacept treatment, while circulating B lymphocyte counts appeared not to be affected by alefacept.

Pharmacokinetic Properties

In patients with moderate to severe plaque psoriasis, following a 7.5 mg intravenous (IV) administration, the mean volume of distribution of alefacept was 94 mL/kg, the mean clearance was 0.25 mL/h/kg, and the mean elimination half-life was approximately 270 hours. Following an intramuscular (IM) injection, bioavailability was 63%.

The pharmacokinetics of alefacept in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alefacept have not been studied.