Treatment of Inflammatory Macular Edema with Humanized Anti-CD11a Antibody Therapy

Cystoid macular edema (CME) is seen in 33% of patients with uveitis and requires local or systemic treatment for resolution.1 Standard systemic immunosuppressive medications can be associated with significant adverse effects.2–4 Management and prevention of the iatrogenic complications of immunosuppressive therapy accounts for most of the medical resources devoted to these individuals. Consequently, an effective treatment with a safer side effect profile is highly desirable. Efalizumab (Raptiva; Genentech Inc., San Francisco, CA) is a humanized form of a murine IgG1 antibody directed against CD11a, the α-subunit of lymphocyte function–associated antigen-1 (LFA-1).5 LFA-1 expression is increased in memory T-cells, and ICAM-1 is expressed on vascular endothelial cells at sites of inflammation in a variety of T-cell-mediated disorders, including uveitis.6 Both LFA-1 and intercellular adhesion molecule (ICAM)-1 are thought to play important roles in the pathogenesis of autoimmune disorders, and prior studies have shown that interference with adhesion molecule function, including CD11a, decreases histologic and clinical expression of endotoxin-induced uveitis.7,8 In vitro studies have shown that by binding to CD11a, efalizumab can inhibit T-cell activation, T-cell trafficking, and T-cell adhesion without depleting the T cells.9 Efalizumab was approved for use in moderate to severe plaque psoriasis in adults.10–12 Human NK cells have typically been identified as CD56+CD3− lymphocytes, with two subsets of human NK cells identified based on expression levels of cell surface CD56, CD56dim, and CD56bright.13–15 CD56bright regulatory NK cells have been proposed to play a regulatory role in immune responses based on their lower cytotoxic potential, higher secretion of downregulatory cytokines, and unique surface receptor expression profile.14,16–18 Previous studies have demonstrated that a low-dose infusion of recombinant human IL-2 selectively induces the CD56bright regulatory NK subset.19 Studies in the Laboratory of Immunology of the National Eye Institute and other work have revealed that infusion of daclizumab, a humanized IL-2R (CD25)-blocking antibody, also induces upregulation of this subset in both uveitis and multiple sclerosis.20,21 Patients with active uveitis had a significantly lower level of CD56bright regulatory NK cells in their peripheral blood compared with normal donors.20 The expansion of CD56bright cells correlates with decreased ocular and brain inflammation.20,21 Induced CD56bright regulatory NK cells have the ability to secrete large amounts of IL-10, whereas CD56dim NK cells do not, suggesting that the induction of the CD56bright regulatory NK cells may have a beneficial effect on the remission of active uveitis.20 This study was designed to evaluate the safety and potential efficacy of subcutaneous humanized anti-CD11a antibody treatments for macular edema associated with uveitis, while reducing or eliminating standard medications commensurate with the standard of care.