Abstract 1458: Application of a Targeted Immunocytokine Reduces Plaque Formation and Macrophage Content in Aortic Lesions from ApoE-Deficient Mice
It has been demonstrated that the angiogenic matrix protein ED-B fibronectin (ED-B) is upregulated in atherosclerotic lesions and various tumors and can be targeted using antibody conjugates. In the present study we used a newly developed fusion protein (L19-Il2) consisting of an anti-ED-B single chain antibody and the active cytokine interleukin-2 (Il2), which is a potent antitumor agent. The effect of this fusion protein delivering Il-2 locally to atherosclerotic tissue is unclear. Therefore we investigated the short term application of L19-Il2 on lesion formation in ApoE(−/−)mice. 6-month old ApoE(−/−) mice, fed with normal diet (n=6/group) were injected intravenously with 4290 IU L19-Il2/g bodyweight or PBS at day 1, 3 and 5 and were sacrificed at day 7. Plaque lesion formation was analyzed by histology, immunohistochemistry (Mac3=macrophages, CD31; actin, ED-B), morphometry of the aortic root and by sudan stain of the thoracic aorta followed by densitometry. Macrophage and ED-B content was analysed after immunohistochemistry using densitometric analysis.
Results: Treatment with L19-Il2 did not affect bodyweight and survival of mice compared to control group. Serum levels for blood glucose, cholesterol, cardiac enzymes and troponin were not different between both groups. Cardiac histology was also unaffected. The aortic lesion areas, analysed by sudan staining were not significantly different (L19-Il2: 13.3 ±4.3%, control: 15.2 ±3.6%). L19-Il2 application significantly reduced plaque lesion size in the aortic roots (L19-Il2: 1.7±0.8%, control: 4.2±1.1%, p<0.01), ED-B expression in the lesions (L19-Il2: 16.3±2.2%, control: 46±8.2%, p<0.01), and Mac3 immunoreactivity (L19-Il2: 1.9±0.5%, control: 4.8 ±0.7%, p<0.01). ED-B and Mac3 could be clearly attributed to different cell types. There was a significant correlation between Mac3 and ED-B the aortic plaque lesions (r=0.63, P<0.001) indicating that inflammation is upregulating the expression of ED-B.
Conclusion: Using a targeted immunocytokine we observed a significantly reduced atherosclerotic lesion size in the aortic root as well as lesion macrophage content. The present study suggests that a antitumor concept might be also effective for the treatment of atherosclerotic disease.