DDR1 has been identified as a cancer-associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi-kinase inhibitors, such as nilotinib, inhibit DDR1-mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody-based strategy with a novel anti-DDR1 antibody-drug conjugate (ADC) for colon carcinoma treatment. We developed T4 H11 -DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro, T4 H11 -DM4 exhibited potent anti-proliferative activity with half maximal inhibitory concentration (IC50 ) values in the nanomolar range in a panel of colon cancer cell lines. In vivo, the antitumor efficacy of T4 H11 -DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T4 H11 -DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg-1 in HT-29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T4 H11 -DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T4 H11 -DM4 was efficacious in oxaliplatin-resistant colon cancer models. In exploratory safety studies, T4 H11 -DM4 exhibited no overt toxicities when multi-doses were administered at 10 mg·kg-1 into BALB/c nude mice or when a single dose up to 50 mg·kg-1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1-targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

中文翻译：

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用抗体-药物偶联物靶向DDR1在结肠癌的小鼠模型中具有抗肿瘤作用。

DDR1已被鉴定为与癌症相关的受体酪氨酸激酶，相对于正常组织在多种恶性肿瘤中高表达。临床批准的多激酶抑制剂（例如尼罗替尼）在异种移植模型中抑制DDR1介导的肿瘤生长，这表明DDR1可能是癌症治疗的潜在靶标。在这里，我们采用了基于抗体的策略，将新型抗DDR1抗体-药物偶联物（ADC）用于结肠癌的治疗。我们开发了T4 H11 -DM4，这是一种针对DDR1的ADC，其携带微管蛋白抑制剂有效载荷DM4。对包含100个结肠癌标本的组织微阵列进行的免疫组织化学分析表明，DDR1在81％的肿瘤组织中高度表达。同时，DDR1的高表达与患者生存不良有关。体外，T4 H11 -DM4表现出有效的抗增殖活性，在一组结肠癌细胞系中纳摩尔浓度范围内的最大抑制浓度（IC50）值为一半。在体内，在表达不同水平的DDR1的三种结肠癌细胞系中评估了T4 H11 -DM4的抗肿瘤功效。T4 H11 -DM4在HT-29和HCT116肿瘤模型中以5和10 mg·kg-1的剂量实现了完全的肿瘤消退。此外，观察到T4 H11 -DM4的体内功效与细胞表面上的DDR1表达水平之间的相关性。肿瘤细胞的增殖是由有丝分裂阻滞的诱导引起的，表明体内的抗肿瘤作用是由DM4介导的。另外，T4 H11 -DM4在抗奥沙利铂的结肠癌模型中有效。在探索性安全研究中，当以10 mg·kg-1的剂量向BALB / c裸鼠多剂量给药或以50 mg·kg-1的单剂量向BALB / c小鼠给药时，T4 H11 -DM4没有明显的毒性。总体而言，我们的发现突出了以DDR1为靶点的ADC的潜力，并可能促进结肠癌新的有效治疗策略的发展。