Targeting of DDR1 with antibody-drug conjugates has antitumor effects in a mouse model of colon carcinoma.

Abstract

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.

• Authors: Yiran Tao, Ruixue Wang, Qinhuai Lai, Mengdan Wu, Yuxi Wang, Xiaohua Jiang, Lishi Zeng, Shijie Zhou, Zhongping Li, Tinghan Yang, Yuqin Yao, Yangping Wu, Lin Yu, Yuyin Fu, Weirong Lai, Yujia Peng, Ying Lu, Zhixiong Zhang, Cuiyu Guo, Guangbing Zhang, Lantu Gou, Jinliang Yang
• Journal: Molecular oncology (Mol Oncol) Vol. 13 Issue 9 Pg. 1855-1873 (09 2019) ISSN: 1878-0261 [Electronic] United States
• PMID: 31116512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents, Immunological
• Immunoconjugates
• Neoplasm Proteins
• DDR1 protein, human
• Discoidin Domain Receptor 1

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Caco-2 Cells
• Discoidin Domain Receptor 1 (antagonists & inhibitors, metabolism)
• Drug Delivery Systems
• HCT116 Cells
• HT29 Cells
• Humans
• Immunoconjugates (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays