Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nat Commun. 2021 Jun 10;12(1):3528. doi: 10.1038/s41467-021-23793-7.
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.
乳腺肿瘤通常由具有不同基因表达谱的多种细胞组成。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。抗体药物偶联物（ADC）是一种新兴的化疗药物，具有显著的临床疗效，包括用于 HER2 阳性乳腺癌的 T-DM1。然而，这些 ADC 经常受到与肿瘤内异质性相关的问题的困扰。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。我们的缀合物表现出针对 HER2 的细胞杀伤效力、理想的药代动力学特征、最小的炎症反应和在治疗剂量下的轻微毒性。值得注意的是，双药物 ADC 在异种移植小鼠模型中比两种单药物变体的联合给药具有更大的治疗效果和生存获益，这些模型代表了肿瘤内 HER2 异质性和升高的耐药性。我们的研究结果强调了双药物 ADC 格式在治疗难治性乳腺癌及其他癌症方面的治疗潜力。
