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