EFALIZUMABUM

Description

Efalizumab, a humanized monoclonal antibody marketed for the treatment of psoriasis, is a full-length IgG1 antibody developed through a murine anti-human CD11a mAb. It is produced in a Chinese hamster ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin. Psoriasis is a disease mediated through inflammatory cells (primarily T-cells expressing CD4 or CD8 markers) and keratinocytes. CD11a is the alpha-chain LFA-1 (leukocyte function associate antigen; integrin family). It is expressed on the surface of Tlymphocytes and it binds to the intercellular cell adhesion molecules (ICAM-1, -2 and -3) on endothelial cells, monocytes, keratinocytes, fibroblasts, and activated lymphocytes. By blocking LFA-1 binding the ability of T cells to adhere, migrate and be activated is blunted. Studies in chimpanzee and murine animal models demonstrated that efalizumab down regulates the expression of LFA-1 on lymphocytes, prevents contact dermatitis to 2,4-dinitrofluorobenzene, increases skin and heart transplant survival. In the collagen-induced arthritis model it delays onset and decreases the severity of the arthritic condition. In a study of 498 patients, efalizumab treatment of 1 or 2 mg/kg/wk for 12 weeks provided, respectively, a 39 or 27% Psoriasis Area and Severity Score (PASI) improvement of ≥75%. By comparison, placebo provided a 2% improvement. It was further demonstrated that a second 12-week course could provide additional improvement. As dose increases, clearance decreases (dose 0.1 mg/kg: 322 ml/day/kg; dose 10 mg/kg: 6.6 mL/day/kg) with data suggesting saturation of clearance above 10 mg/mL. A pharmacokinetic model positively correlates number of circulating cells expressing CD11a with relative clearance. This blockade decreases the CD11a expressed on circulating lymphocytes to about 25% of their baseline levels in patients with plaque psoriasis. Efalizumab is formulated as a once-weekly subcutaneous injectable, dosed at 0.7 to 1 mg/kg/week. Although mild adverse events were noted such as headache, pain chills, nausea, and fever, these events generally decreased after one or two doses. The overall rate of infections was only 3% higher than the placebo-arm and no depletion of T-cells was noted.

Originator

XOMA (US)

Uses

Treatment of transplant rejections; antipsoriatic (immunomodulator monoclonal antibody which decreases the activation, migration, and adhesion of T-cells). hu1124; anti-CD11a.

brand name

Raptiva

in vivo