Nat Commun:双药抗体-药物偶联物:对抗乳腺癌的异质性和耐药性的利器

2021-06-13 xiaozeng MedSci原创

乳腺癌是一种异质性疾病,由具有不同基因表达谱的不同细胞群所引起。

乳腺癌是一种异质性疾病,由具有不同基因表达谱的不同细胞群所引起。乳腺癌的肿瘤间和肿瘤内异质性是导致该疾病化疗后复发和转移的主要因素,乳腺癌的化疗往往伴随着对初始治疗中使用的治疗药物的获得性耐药。

既往研究显示,HER2(人表皮生长因子受体2)在14-20%的乳腺癌患者中过表达。而在16-36%的HER2阳性乳腺癌患者中观察到HER2表达的肿瘤内异质性。HER2的异质性与肿瘤的侵袭性生长、高复发率以及患者较差的存活率相关。

此外,在用曲妥珠单抗持续治疗后,HER2的表达水平会出现降低,并导致对抗HER2治疗产生耐药性。因此,HER2的异质性是使用HER2靶向药物实现真正有效治疗的一个巨大阻碍。


抗体-药物偶联物(ADCs)是一种新兴的化疗药物,其临床上取得了惊人的成功,包括用于治疗HER2阳性乳腺癌的药物T-DM1。然而,这些ADCs也经常受到与肿瘤内异质性相关的问题的困扰。

双药ADC合成的分子设计与偶联策略

在该研究中,研究人员发现,包含两种不同有效载荷的同源ADC是解决这一临床挑战的一种有前途的药物类别。该偶联物在治疗剂量下显示出对HER2特异性细胞的杀伤效力、理想的药代动力学特征、最小的炎症反应和边缘毒性。


值得注意的是,在表现肿瘤内HER2异质性和耐药性升高的移植瘤小鼠模型中,双药ADC相比于联合使用两种单药变体具有更大的治疗效果和生存益处。

双药ADC的构建与表征

总而言之,该研究结果揭示了双药ADC在治疗难治性乳腺癌和其他癌症方面的治疗潜力。


原始出处:

Yamazaki, C.M., Yamaguchi, A., Anami, Y. et al. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun 12, 3528 (10 June 2021).

 

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    2021-11-16 liuli5079
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    2021-06-14 ms9000000883963153

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