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  3. Synergistic approach to combating triple-negative breast cancer: DDR1-targeted antibody-drug conjugate combined with pembrolizumab

Synergistic approach to combating triple-negative breast cancer: DDR1-targeted antibody-drug conjugate combined with pembrolizumab

  • J Pharm Anal. 2025 May;15(5):101100. doi: 10.1016/j.jpha.2024.101100.
Shoubing Zhou 1 2,  Wenyu Li 1 2,  Dan Zhao 3,  Qiujun Zhang 1 2,  Hu Liu 1 2,  Tengchuan Jin 3 4 5,  Yueyin Pan 1 2
Affiliations

Affiliations

  • 1 Department of Breast Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China.
  • 2 Department of Breast Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China.
  • 3 Laboratory of Structural Immunology, The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
  • 4 Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of International Health and Medicine (IHM), University of Science and Technology of China, Hefei, 230001, China.
  • 5 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230027, China.
PMID: 40521369 DOI: 10.1016/j.jpha.2024.101100
Abstract

Discoidin Domain Receptor 1 (DDR1) is overexpressed in various tumors, such as triple-negative breast Cancer (TNBC), and is rarely expressed in normal tissues. These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate (ADC) for targeted therapy. Here, we investigated the preparation and preclinical efficacy of DDR1-DX8951, an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly (GGFG) linker. The anti-DDR1 monoclonal antibody was coupled to DX8951 (i.e., DDR1-DX8951), producing the targeted therapy ADC. The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models. DDR1-DX8951 can specifically target DDR1, be quickly internalized by TNBC cells, and reduce the viability of TNBC cells in vitro. The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models. Importantly, our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment (TME) of TNBC. Taken together, this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.

Keywords

Antibody-drug conjugates; Discoidin domain receptor 1; Immunotherapy; Targeted therapy; Triple negative breast cancer.

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