Targeting of DDR1 with antibody-drug conjugates has antitumor effects in a mouse model of colon carcinoma
Targeting of DDR1 with antibody-drug conjugates has antitumor effects in a mouse model of colon carcinoma
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使用抗体药物缀合物靶向 DDR 1 在结肠癌小鼠模型中具有抗肿瘤作用
DOI：
10.1002/1878-0261.12520
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发表时间：
2019-07-22
影响因子：
6.6
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
--
作者：
Tao, Yiran;Wang, Ruixue;Yang, Jinliang
DDR1是一种与癌症相关的受体酪氨酸激酶，在多种恶性肿瘤组织中相对正常组织中高表达。临床批准的多激酶抑制剂，如尼洛替尼，在异种移植模型中抑制DDR1介导的肿瘤生长，表明DDR1可能是癌症治疗的潜在靶点。在这里，我们采用了一种基于抗体的策略和一种新型的抗DDR1抗体-药物结合物(ADC)来治疗结肠癌。我们开发了T4H11-dm4，一种针对携带微管蛋白抑制剂有效载荷dm4的DDR1的ADC。对包含100个结肠癌标本的组织芯片的免疫组织化学分析表明，DDR1在81%的肿瘤组织中高表达。同时，DDR1的高表达与患者的生存不良有关。在体外，T4H11-dm4在一组结肠癌细胞系中显示出强大的抗增殖活性，其半数最大抑制浓度(IC50)值在纳摩尔范围内。在体内，T4H11-dm4对三种表达不同水平的DDR1的结肠癌细胞株的抗肿瘤效果进行了评估。在HT-29和HCT116肿瘤模型中，T4H11-dm4在5和10 mg中心点kg(-1)剂量下肿瘤完全消退。此外，还观察到T4H11-dm4的体内效应与细胞表面DDR1表达水平的相关性。肿瘤细胞的增殖是由诱导有丝分裂停滞引起的，表明体内的抗肿瘤作用是由dm4介导的。此外，T4H11-dm4对奥沙利铂耐药的结肠癌模型有较好的疗效。在探索性安全性研究中，T4H11-dm4在BALB/c裸鼠体内以10 mg中心点kg(-1)多次给药或在BALB/c小鼠单次给药至50 mg中心点kg(-1)时均未表现出明显的毒性。总体而言，我们的发现突出了DDR1靶向ADC的潜力，并可能有助于开发一种新的有效的结肠癌治疗策略。
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 T4H11-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, T4H11-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 T4H11-DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T4H11-DM4 achieved complete tumor regression at doses of 5 and 10 mg center dot kg(-1) in HT-29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T4H11-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, T4H11-DM4 was efficacious in oxaliplatin-resistant colon cancer models. In exploratory safety studies, T4H11-DM4 exhibited no overt toxicities when multi-doses were administered at 10 mg center dot kg(-1) into BALB/c nude mice or when a single dose up to 50 mg center dot 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.