Effects of a second-generation human anti-ErbB2 ImmunoRNase on trastuzumab-resistant tumors and cardiac cells
Effects of a second-generation human anti-ErbB2 ImmunoRNase on trastuzumab-resistant tumors and cardiac cells
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DOI：
10.1093/protein/gzt065
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发表时间：
2014-03-01
影响因子：
2.4
通讯作者：
De Lorenzo, Claudia
中科院分区：
文献类型：
--
作者：
D'Avino, Chiara;Paciello, Rolando;De Lorenzo, Claudia
利用人抗体抑制ErbB2可能是治疗乳腺癌和胃癌的一种有价值的策略。曲妥珠单抗是一种临床使用的人源抗erbb2抗体，是有效的，但可能产生耐药性和心脏毒性。由人抗erbb2 scFv和人胰腺核糖核酸酶（HP-RNases）组成的ImmunoRNases已被设计用于克服其他免疫毒素的限制，如免疫原性和非特异性毒性。在这里，我们报告了一种新的抗erbb2免疫nase，称为erbhpddaddd - rnase，通过融合Erbicin（一种人类erbb2定向scFv）与HP-RNase变体抵抗细胞质抑制剂蛋白而获得，与erbb2阳性胃肿瘤细胞组高亲和力结合，并比亲本免疫nase更能抑制其生长，后者对抑制剂无抗性。此外，ErbHP-DDADD-RNase在体外和体内都具有抗曲妥珠单抗耐药癌细胞的抗增殖活性，比亲本免疫nase更有效。重要的是，ErbHP-DDADD-RNase在体外对人类心肌细胞没有显示出心脏毒性作用，并且在小鼠模型中也不会损害心功能。因此，ErbHP-DDADD-RNase可以满足因原发性或获得性曲妥珠单抗耐药或心功能障碍而不适合曲妥珠单抗治疗的癌症患者的治疗需求。
The inhibition of ErbB2 by the use of human antibodies can be a valuable strategy for the treatment of breast and gastric cancer. Trastuzumab, a humanized anti-ErbB2 antibody in clinical use, is effective but can engender resistance as well as cardiotoxicity. ImmunoRNases, made up of a human anti-ErbB2 scFv and human pancreatic ribonucleases (HP-RNases), have been engineered to overcome the limits of other immunotoxins, such as immunogenicity and nonspecific toxicity. Here, we report that a novel anti-ErbB2 immunoRNase, called ErbHPDDADD-RNase, obtained by fusing Erbicin, a human ErbB2-directed scFv, with an HP-RNase variant that resists the cytosolic inhibitor protein, binds with high affinity to a panel of ErbB2-positive gastric tumor cells and inhibits their growth more than does the parental immunoRNase, which is not resistant to the inhibitor. Moreover, ErbHP-DDADD-RNase is endowed with antiproliferative activity for trastuzumab-resistant cancer cells both in vitro and in vivo that is more potent than that of the parental immunoRNase. Importantly, ErbHP-DDADD-RNase does not show cardiotoxic effects in vitro on human cardiomyocytes and does not impair cardiac function in a mouse model. Thus, ErbHP-DDADD-RNase could fulfil the therapeutic need of cancer patients ineligible for trastuzumab treatment due to primary or acquired trastuzumab resistance or to cardiac dysfunction.