Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody.
BACKGROUND
Leukocyte function-associated antigen 1 (LFA-1), consisting of CD11a and CD18 subunits, plays an important role in T-cell activation and leukocyte extravasation.


OBJECTIVE
To test whether blocking CD11a decreases immunobiologic and clinical activity in psoriatic plaques.


METHODS
Open-label, multicenter, dose escalation study.


METHODS
Thirty-nine patients with moderate-to-severe psoriasis.


METHODS
Intravenous infusions of efalizumab, a humanized anti-CD11a monoclonal antibody, for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (category 1), 0.3 mg/kg weekly (category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (category 3). Skin biopsies were performed on days 0, 28, and 56.


METHODS
Serum efalizumab levels, levels of total and unoccupied T-cell CD11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index (PASI) scores.


RESULTS
Dose-response relationships were observed for pharmacokinetics and pharmacodynamic measures. Category 1 failed to maintain detectable serum efalizumab or T cell CD11a down-modulation between doses. Category 2 achieved both. Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses. A dose-response relationship was also observed clinically and histologically. The mean decrease in the PASI score was 47% in category 3, 45% in category 2, and 10% in category 1 (P<.001). Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16 expression decreased in categories 2 and 3 but not in category 1. Circulating lymphocyte counts increased in categories 2 and 3.


CONCLUSIONS
At doses of 0.3 mg/kg or more per week, intravenous efalizumab produced significant clinical and histologic improvement in psoriasis, which correlated with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation.
Gottlieb
Alice B
AB
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Clinical Research Center, New Brunswick, NJ 08903-0019, USA. gottliab@UMDNJ.EDU
Krueger
James G
JG
Wittkowski
Knut
K
Dedrick
Russell
R
Walicke
Patricia Ann
PA
Garovoy
Marvin
M
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D018655:Lymphocyte Count; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D012449:Safety; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens; D018821:CD18 Antigens; C472181:efalizumab