Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.
Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.
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DOI：
10.1038/s41467-021-23793-7
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发表时间：
2021-06-10
影响因子：
16.6
通讯作者：
Tsuchikama K
中科院分区：
文献类型：
--
作者：
Yamazaki CM;Yamaguchi A;Anami Y;Xiong W;Otani Y;Lee J;Ueno NT;Zhang N;An Z;Tsuchikama K
乳腺肿瘤通常由具有不同基因表达谱的不同细胞群组成。乳腺肿瘤异质性是导致化疗后耐药、复发和转移的主要因素。抗体-药物缀合物（ADC）是具有显著临床成功的新兴化学治疗剂，包括用于HER 2阳性乳腺癌的T-DM 1。然而，这些ADC经常遭受与肿瘤内异质性相关的问题。在这里，我们表明含有两种不同有效载荷的均质ADC是解决这一临床挑战的有前途的药物类别。我们的缀合物显示出HER 2特异性细胞杀伤效力、理想的药代动力学特征、最小的炎症反应和治疗剂量下的边际毒性。值得注意的是，在代表瘤内HER 2异质性和耐药性升高的异种移植小鼠模型中，双药ADC比两种单药变体的共同施用发挥更大的治疗效果和生存益处。我们的研究结果强调了双药ADC形式治疗难治性乳腺癌和其他癌症的治疗潜力。乳腺癌中的肿瘤内异质性可能限制抗体-药物缀合物（ADC）的临床成功。在这项研究中，作者开发了双有效载荷Her 2-ADC，其在体内对异质性乳腺肿瘤显示出有效的抗肿瘤活性。
Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers. Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.
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