Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor b–Expressing Macrophages

Background-—Folate receptor b (FRb) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated Pseudomonas exotoxin A (PE38) conjugated to an anti-FRb antibody (anti–FRb-PE38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting FRb on atherosclerosis, we determined the presence of FRb-expressing macrophages in atherosclerotic lesions and administered the FRb immunotoxin in apolipoprotein E–deficient mice. Methods and Results-—The FRb-expressing macrophages were observed in atherosclerotic lesions of apolipoprotein E–deficient mice. At 15 or 35 weeks of age, the apolipoprotein E–deficient mice were divided into 3 groups and were intravenously administered 0.1 mg/kg of anti–FRb-PE38 (immunotoxin group), 0.1 mg/kg of PE38 (toxin group), or 0.1 mL of saline (control group) every 3 days, for a total of 5 times for each age group. The mice were analyzed at 21 or 41 weeks of age. Treatment with the immunotoxin resulted in 31 % and 22 % reductions in atherosclerotic lesions of the 21- and 41-week-old mice, respectively (P<0.05). Administration of immunotoxin reduced the numbers of FRb- and tumor necrosis factor-a–expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (P<0.05). Real-time polymerase chain reaction demonstrated that the expression of FRb and tumor necrosis factor-a mRNA was significantly decreased in the immunotoxin group (P<0.05). Conclusions-—These results suggest that FRb-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that FRb immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant FRb immunotoxin targeting activated macrophages could provide a novel therapeutic tool fo