Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria
Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria
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DOI：
10.1182/blood-2013-11-536573
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发表时间：
2014-03-27
期刊：
影响因子：
20.3
通讯作者：
Lambris, John D.
中科院分区：
文献类型：
--
作者：
Risitano, Antonio M.;Ricklin, Daniel;Lambris, John D.
阵发性睡眠性血红蛋白尿症（PNH）的特征是由于受影响的红细胞上缺乏CD 55和CD 59而导致补体介导的血管内溶血。抗C5抗体依库珠单抗已被证明具有临床有效性，但由于CD 55缺失导致的不受控制的C3活化可能导致红细胞调理作用，可能导致具有临床意义的血管外溶血。我们研究了肽C3抑制剂坎普他汀Cp 40及其长效形式（聚乙二醇[PEG]-Cp 40）在已建立的体外系统中对PNH红细胞溶血和调理作用的影响。两种化合物均表现出溶血的剂量依赖性抑制，IC 50与4 μ M相似，在6 μ M时完全抑制。Cp 40或PEG-Cp 40的保护水平也有效地防止了C3片段在PNH红细胞上的沉积。我们进一步探索了这两种抑制剂全身给药的潜力，并在非人灵长类动物中进行了药代动力学评价。PEG-Cp 40的单次静脉内注射导致>5天的延长的消除半衰期，但可能潜在地影响C3的血浆水平。尽管消除动力学更快，但通过重复皮下给药，未修饰的Cp 40可达到饱和抑制剂浓度。总之，C3激活的肽抑制剂有效地防止溶血和PNH红细胞的C3调理作用，并且是用于进一步临床研究的优秀的且潜在的成本有效的候选者。
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the lack of CD55 and CD59 on affected erythrocytes. The anti-C5 antibody eculizumab has proven clinically effective, but uncontrolled C3 activation due to CD55 absence may result in opsonization of erythrocytes, possibly leading to clinically meaningful extravascular hemolysis. We investigated the effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system. Both compounds demonstrated dose-dependent inhibition of hemolysis with IC50 similar to 4 mu M and full inhibition at 6 mu M. Protective levels of either Cp40 or PEG-Cp40 also efficiently prevented deposition of C3 fragments on PNH erythrocytes. We further explored the potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates. A single intravenous injection of PEG-Cp40 resulted in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration. In conclusion, peptide inhibitors of C3 activation effectively prevent hemolysis and C3 opsonization of PNH erythrocytes, and are excellent, and potentially cost-effective, candidates for further clinical investigation.