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

Autor: Shijie Zhou, Mengdan Wu, Yujia Peng, Lin Yu, Cuiyu Guo, Ruixue Wang, Lantu Gou, Weirong Lai, Ying Lu, Jinliang Yang, Tinghan Yang, Xiaohua Jiang, Yiran Tao, Guangbing Zhang, Yuxi Wang, Lishi Zeng, Yangping Wu, Qinhuai Lai, Zhongping Li, Zhixiong Zhang, Yuqin Yao, Yuyin Fu
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Immunoconjugates
Colorectal cancer
Cell
Receptor tyrosine kinase
Mice
Antineoplastic Agents
Immunological
Drug Delivery Systems
0302 clinical medicine
Research Articles
Mice
Inbred BALB C
Tissue microarray
biology
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoplasm Proteins
medicine.anatomical_structure
colon cancer
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
HT29 Cells
Research Article
antibody‐drug conjugate
medicine.drug
Antibody-drug conjugate
Mice
Nude
lcsh:RC254-282
resistance
03 medical and health sciences
Discoidin Domain Receptor 1
In vivo
Genetics
medicine
Animals
Humans
business.industry
Cancer
Neoplasms
Experimental
HCT116 Cells
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Nilotinib
receptor tyrosine kinase
Cancer research
biology.protein
Caco-2 Cells
business
xenograft tumor model
Zdroj: Molecular Oncology
Molecular Oncology, Vol 13, Iss 9, Pp 1855-1873 (2019)
ISSN: 1878-0261
1574-7891
Popis: 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.
Databáze: OpenAIRE
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