Zhou Shoubing, Li Wenyu, Zhao Dan, Zhang Qiujun, Liu Hu, Jin Tengchuan, Pan Yueyin
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.
Department of Breast Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China.
J Pharm Anal. 2025 May;15(5):101100. doi: 10.1016/j.jpha.2024.101100. Epub 2024 Sep 13.
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 . 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.
盘状结构域受体1（DDR1）在多种肿瘤中过表达，如三阴性乳腺癌（TNBC），而在正常组织中很少表达。这些特性使DDR1成为构建用于靶向治疗的抗体药物偶联物（ADC）的理想靶点候选物。在此，我们研究了DDR1-DX8951的制备及其临床前疗效，DDR1-DX8951是一种ADC，它包含通过可裂解的甘氨酰-甘氨酰-苯丙氨酰-甘氨酸（GGFG）连接子与DX8951偶联的抗DDR1单克隆抗体。将抗DDR1单克隆抗体与DX8951偶联（即DDR1-DX8951），制备出靶向治疗ADC。在TNBC小鼠模型中评估了DDR1-DX8951单药治疗或DDR1-DX8951联合帕博利珠单抗的抗肿瘤活性。DDR1-DX8951可以特异性靶向DDR1，被TNBC细胞快速内化，并降低TNBC细胞的活力。DDR1-DX8951在TNBC异种移植模型中显示出强大的抗肿瘤活性。重要的是，我们的研究表明，DDR1-DX8951联合帕博利珠单抗不仅显示出对肿瘤生长和转移的抑制作用，而且在改善TNBC的免疫抑制肿瘤微环境（TME）方面也发挥了重要作用。综上所述，本研究为进一步评估DDR1-DX8951联合帕博利珠单抗用于TNBC临床试验的安全性和疗效的大样本研究提供了依据。
