上海交通大学Jian-wei Zhu等研究人员合作发现，靶向HER2和HER3的新型双特异性抗体药物共轭物对乳腺癌具有强大疗效。2024年4月11日，《中国药理学报》杂志在线发表了这项成果。

研究人员构建了一种HER2/HER3靶向双特异性抗体药物偶联物（BsADC），在体外对其理化性质、靶向特异性和内化进行了表征，并在乳腺癌细胞系和动物模型中评估了其抗肿瘤活性。HER2/HER3靶向BsADC的药物抗体比（DAR）为2.89，在体外对靶向JIMT-1乳腺癌细胞具有高选择性，内化水平也略高于HER2或HER3单特异性抗体药物偶联物（ADC）。

更重要的是，这种双特异性ADC在体外能有效抑制MCF7、JIMT-1、BT474、BxPC-3 和 SKOV-3癌细胞的活力。在JIMT-1乳腺癌异种移植小鼠中，单次注射双特异性ADC（3毫克/千克，静脉注射）可显著抑制肿瘤生长，其疗效与联合注射HER2和HER3单特异性ADC（各3毫克/千克）的疗效相当。该研究表明，双特异性ADC概念可用于开发比单特异性ADC更有效的新型癌症疗法。

据悉，ADC疗法已成为癌症免疫疗法中最有前途的方法之一。双特异性靶向可以提高ADC的特异性、亲和力和内化能力，从而增强其疗效和安全性。

附：英文原文

Title: A novel bispecific antibody drug conjugate targeting HER2 and HER3 with potent therapeutic efficacy against breast cancer

Author: Zong, Hui-fang, Li, Xi, Han, Lei, Wang, Lei, Liu, Jun-jun, Yue, Ya-li, Chen, Jie, Ke, Yong, Jiang, Hua, Xie, Yue-qing, Zhang, Bao-hong, Zhu, Jian-wei

Issue&Volume: 2024-04-11

Abstract: Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.

DOI: 10.1038/s41401-024-01279-8

Source: https://www.nature.com/articles/s41401-024-01279-8