Darvishi B, Farahmand L, Jalili N, Majidzadeh-A K
Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Tasnim Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.
Curr Mol Med. 2018;18(5):335-342. doi: 10.2174/1566524018666181004120112.
Antibody-toxin fused agents or immunotoxins, are a newly engineered class of cytotoxic agents consisting of a bacterial or plant toxin moiety hooked up either to a monoclonal antibody or a specific growth factor. Nevertheless, acquiring a full potency in clinic is mostly restricted due to the Capillary leak syndrome (CLS), a serious immune provoked, life-threatening side effect, subsequent to the endothelial damage, resulting in fluid escape from the bloodstream into tissues including lungs, muscle and brain, developing organ failure and eventually death. Proposed underlying mechanisms include direct damage to endothelial cells, acute inflammation, Lymphokine-activated killer (LAK) cells engagement, alteration in cell-cell/cell-matrix connectivities and cytoskeletal dysfunction. Very poor biodistribution and heterogeneous extravasation pattern in tumor site result in accumulation of ITs close to the extravasation site, gradual toxin release and initiation of nearby endothelial cells lysis, secretion of pro-inflammatory cytokines, development of acute inflammation and engagement of Lymphokine-activated killer (LAK) cells. Intrinsic immunogenicity of applied toxin moiety is another important determinant of CLS incidence. Toxins with more intrinsic immunogenicity possess more probability for CLS development. Recently, development of new generations of antibodies and mutated toxins with conserved cytotoxicity has partly tapered risk of CLS development. Here, we describe probable mechanisms involved in CLS and introduce some of the recently applied strategies for lessening incidence of CLS as much as possible.
抗体 - 毒素融合剂或免疫毒素是一类新设计的细胞毒性药物，由与单克隆抗体或特定生长因子相连的细菌或植物毒素部分组成。然而，由于毛细血管渗漏综合征（CLS），这类药物在临床上充分发挥效力大多受到限制。CLS是一种严重的、由免疫引发的、危及生命的副作用，继发于内皮损伤，导致液体从血液渗入包括肺、肌肉和脑在内的组织，进而引发器官衰竭并最终导致死亡。其潜在机制包括对内皮细胞的直接损伤、急性炎症、淋巴因子激活的杀伤（LAK）细胞的参与、细胞间/细胞与基质连接的改变以及细胞骨架功能障碍。在肿瘤部位极差的生物分布和异质性渗出模式导致免疫毒素在渗出部位附近积聚，毒素逐渐释放并引发附近内皮细胞裂解、促炎细胞因子的分泌、急性炎症的发展以及淋巴因子激活的杀伤（LAK）细胞的参与。所应用毒素部分的内在免疫原性是CLS发生率另一个重要的决定因素。具有更高内在免疫原性的毒素发生CLS的可能性更大。最近，新一代具有保守细胞毒性的抗体和突变毒素的开发在一定程度上降低了CLS发生的风险。在此，我们描述了CLS涉及的可能机制，并介绍了一些最近应用的尽可能降低CLS发生率的策略。
