**7.2.1 Alefacept**

Alefacept, a recombinant dimeric fusion protein, is made up of the terminal portion of leukocyte function antigen-3 (LFA-3). It binds to extracellular human CD2 and the Fc portion of human immunoglobulin IgG1 (Sugiyama et al., 2008). Alefacept blocks signalling between LFA-3 on antigen presenting cells and the CD2 molecule on T cells (primarily CD45RO+).

Subsequently, the activation and proliferation of CD45RO+ T cells, which account for approximately 75% of T lymphocytes in psoriatic lesions, are inhibited. Furthermore, alefacept decreases the number of pathogenic T cells by binding CD2 on CD45RO+ T cells to the FcgIII receptor on natural killer cells, resulting in granzyme-mediated apoptosis of T cells (Gordon et al., 2003; Sobell et al., 2009; Sugiyama et al., 2008). Using a dosage of 15 mg alefacept administered intramuscularly QW, PASI 75 scores at week 12 were found to range between 21 and 35% (Gordon et al., 2003; Pathirana et al., 2009; Sugiyama et al., 2008). Recently, patients receiving alefacept in combination with MTX were shown to improve significantly in ACR 20 at week 24 compared with patients treated with MTX and placebo alone (54% vs. 23%; *P* < 0.001) (Mease et al., 2006a).

#### **7.3 IL-12/IL-23 antagonists**

Briakinumab and ustekinumab are both IL-12/IL-23 antagonists. Whereas briakinumab is currently under investigation for the psoriasis treatment in several phase III studies, ustekinumab was recently approved by the EMEA for the therapy of chronic plaque psoriasis.

#### **7.3.1 Briakinumab (ABT874)**

Briakinumab is a recombinant fully human, IgG1 Moab targeting the shared p40 subunit of IL-12 and IL-23 (Kimball et al., 2008b). It binds to soluble forms of IL-12 and IL-23, leading to a decreased secretion of pro-inflammatory cytokines: IL-12, IL-6, IFN- and TNF-, as shown in CD patients (Ding et al., 2008).

In a phase I trial with 64 healthy controls, the pharmacokinetics of briakinumab (0.1–5.0 mg·kg-1 subcutaneously or intravenously) were evaluated. A linear relationship between the Cmax and AUC (concentration-time) was found with increasing doses. The terminal phase half-life time was about 9 days. No dose dependency was found for the volume distribution at steady state and the clearance of the drug. Subcutaneous and intramuscular application achieved an absolute bioavailability of 42 and 63% respectively (Ding et al., 2008).

A phase II study with briakinumab was conducted (Kimball et al., 2008b) in patients with psoriasis. Patients were randomized in groups of 30 to receive either only one dose of briakinumab 200 mg at week 0, 100 mg briakinumab every other week for 12 weeks, 200 mg weekly for 4 weeks, 200 mg every other week for 12 weeks and 200 mg every week for 12 weeks, or placebo respectively(Kimball et al., 2008b).

PASI 75 was significantly (*P* < 0.001) more often reached in patients in all five briakinumab treatment groups (63, 93, 90, 93, and 90% respectively) compared with the placebo group (3%). Statistically significant improvement to briakinumab therapy was rapid and could be registered in the briakinumab groups as early as at week 1. During the 12-week period, improvement could be sustained in briakinumab-treated patients even for patients in the briakinumab 200 mg x 1 and 200 mg x 4 dosage groups.

Besides injection site reactions, other common side effects the trial study comprised nasopharyngitis and upper respiratory infections. In addition, non-infectious serious adverse events reported in this study included costal chondritis in one patient. Significantly more patients in the briakinumab groups (36%) experienced adverse events compared with the placebo group (10%) (Kimball et al., 2008b).
