Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Circ Cardiovasc Interv. 2012 Apr;5(2):279-87. doi: 10.1161/CIRCINTERVENTIONS.111.967596. Epub 2012 Feb 21.
Toll-like receptor (TLR)-2 is an important mediator of innate immunity and ischemia/reperfusion-induced cardiac injury. We have previously shown that TLR2 inhibition reduces infarct size and improves cardiac function in mice. However, the therapeutic efficacy of a clinical grade humanized anti-TLR2 antibody, OPN-305, in a large-animal model remained to be addressed.
Pigs (n=38) underwent 75 minutes ischemia followed by 24 hours of reperfusion. Saline or OPN-305 (12.5, 6.25, or 1.56 mg/kg) was infused intravenously 15 minutes before reperfusion. Cardiac function and geometry were assessed by echocardiography. Infarct size was calculated as the percentage of the area at risk and by serum Troponin-I levels. Flow cytometry analysis revealed specific binding of OPN-305 to porcine TLR2. In vivo, OPN-305 exhibited a secondary half-life of 8±2 days. Intravenous administration of OPN-305 before reperfusion significantly reduced infarct size (45% reduction, P=0.041) in a dose-dependent manner. In addition, pigs treated with OPN-305 exhibited a significant preservation of systolic performance in a dose-dependent fashion, whereas saline treatment completely diminished the contractile performance of the ischemic/reperfused myocardium.
OPN-305 significantly reduces infarct size and preserves cardiac function in pigs after ischemia/reperfusion injury. Hence, OPN-305 is a promising adjunctive therapeutic for patients with acute myocardial infarction.
Toll 样受体（TLR）-2 是先天免疫和缺血/再灌注诱导的心脏损伤的重要介质。我们之前已经表明，TLR2 抑制可减少小鼠的梗塞面积并改善心脏功能。然而，一种临床级别的人源化抗 TLR2 抗体 OPN-305 在大型动物模型中的治疗效果仍有待解决。
猪（n=38）经历 75 分钟缺血，随后进行 24 小时再灌注。在再灌注前 15 分钟静脉内输注盐水或 OPN-305（12.5、6.25 或 1.56mg/kg）。通过超声心动图评估心功能和几何形状。梗塞面积通过危险区域面积百分比和血清肌钙蛋白 I 水平计算。流式细胞术分析显示 OPN-305 与猪 TLR2 特异性结合。在体内，OPN-305 的二次半衰期为 8±2 天。再灌注前静脉内给予 OPN-305 可显著减少梗塞面积（减少 45%，P=0.041），呈剂量依赖性。此外，OPN-305 治疗的猪在剂量依赖性方式下表现出收缩性能的显著保留，而盐水治疗完全消除了缺血/再灌注心肌的收缩性能。
OPN-305 可显著减少猪缺血/再灌注损伤后的梗塞面积并保护心功能。因此，OPN-305 是急性心肌梗死患者有前途的辅助治疗方法。
