1Department of Anesthesiology, Aarhus University HospitalAarhusDenmark. 2Cytoguide ApS, Incuba Science ParkAarhusDenmark. 3Department of Clinical Biochemistry, Aarhus University HospitalAarhusDenmark. 4Department of Biomedicine, University of AarhusAarhusDenmark.
Crit Care Med. 2013 Nov;41(11):e309-18. doi: 10.1097/CCM.0b013e31828a45ef.
Macrophages are important cells in immunity and the main producers of pro-inflammatory cytokines. The main objective was to evaluate if specific delivery of glucocorticoid to the macrophage receptor CD163 is superior to systemic glucocorticoid therapy in dampening the cytokine response to lipopolysaccharide infusion in pigs.
Two randomized, placebo-controlled trials.
University hospital laboratory.
Female farm-bred pigs (26-31 kg).
A humanized antibody that binds to pig and human CD163 was produced, characterized, and conjugated with dexamethasone. In the first study (total n = 12), pigs were randomly assigned to four groups: 1) saline; 2) dexamethasone (1.0 mg/kg); 3) dexamethasone (0.02 mg/kg); and 4) anti-CD163-conjugated dexamethasone (0.02 mg/kg). In the second study (total n = 36), two additional groups were included in addition to the four original groups: 5) anti-CD163-conjugated dexamethasone (0.005 mg/kg); 6) unconjugated anti-CD163. Treatments were given 20 hours prior to infusion of lipopolysaccharide (1 µg × kg × h) for 5 hours. Blood samples were analyzed for cytokines, cortisol, and adrenocorticotropic hormone.
In the saline group, lipopolysaccharide increased cytokine and plasma cortisol levels. In both studies, dexamethasone (1 mg/kg) and anti-CD163 dexamethasone (0.02 mg/kg) uniformly attenuated tumor necrosis factor-α peak levels (both p < 0.05) compared with low-dose dexamethasone (0.02 mg/kg). However, dexamethasone 1 mg/kg significantly suppressed plasma cortisol and adrenocorticotropic hormone levels compared with anti-CD163 dexamethasone (0.02 mg/kg; p < 0.05). No significant hemodynamic difference existed between groups. The anti-CD163 dexamethasone drug conjugate exhibited a fast plasma clearance, with a half-life of approximately 5-8 minutes.
Targeted delivery of dexamethasone to macrophages using a humanized CD163 antibody as carrier exhibits anti-inflammatory effects comparable with 50 times higher concentrations of free dexamethasone and does not inhibit endogenous cortisol production. This antibody-drug complex showing similar affinity and specificity for human CD163 is, therefore, a promising drug candidate in this novel type of anti-inflammatory therapy.
巨噬细胞是免疫中的重要细胞，也是促炎细胞因子的主要产生者。主要目的是评估将糖皮质激素特异性递送至巨噬细胞受体 CD163 是否优于全身糖皮质激素治疗，以抑制猪脂多糖输注引起的细胞因子反应。
两项随机、安慰剂对照试验。
大学医院实验室。
女性农场饲养的猪（26-31 公斤）。
产生了一种与人及猪 CD163 结合的人源化抗体，对其进行了特征描述，并与地塞米松结合。在第一项研究（共 12 只猪）中，猪被随机分配到四组：1）生理盐水；2）地塞米松（1.0mg/kg）；3）地塞米松（0.02mg/kg）；和 4）抗 CD163 结合的地塞米松（0.02mg/kg）。在第二项研究（共 36 只猪）中，除了四个原始组之外，还包括另外两个组：5）抗 CD163 结合的地塞米松（0.005mg/kg）；6）未结合的抗 CD163。在脂多糖（1μg×kg×h）输注前 20 小时给予治疗，持续 5 小时。分析血液样本中的细胞因子、皮质醇和促肾上腺皮质激素。
在生理盐水组中，脂多糖增加了细胞因子和血浆皮质醇水平。在两项研究中，与低剂量地塞米松（0.02mg/kg）相比，地塞米松（1mg/kg）和抗 CD163 地塞米松（0.02mg/kg）均均匀地减弱了肿瘤坏死因子-α的峰值水平（均 p<0.05）。然而，与抗 CD163 地塞米松（0.02mg/kg）相比，地塞米松 1mg/kg 显著抑制了血浆皮质醇和促肾上腺皮质激素水平（p<0.05）。组间无明显的血流动力学差异。抗 CD163 地塞米松药物偶联物具有快速的血浆清除率，半衰期约为 5-8 分钟。
使用人源化 CD163 抗体作为载体将地塞米松靶向递送至巨噬细胞具有抗炎作用，其效果与 50 倍高浓度的游离地塞米松相当，并且不抑制内源性皮质醇的产生。这种对人 CD163 具有相似亲和力和特异性的抗体药物复合物是这种新型抗炎治疗的有前途的候选药物。
