2. Academic Validation
  3. Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2

Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2

  • Bioorg Med Chem. 2024 Aug 1:110:117828. doi: 10.1016/j.bmc.2024.117828.
Caili Luo 1,  Anni Ren 2,  Zixuan Jin 3,  Jianxin Zhang 4,  Wei Shi 5,  Yue Zeng 5,  Zhaojun Liu 3,  Mengru Lu 3,  Yajing Hou 3,  Feng Tang 6,  Wei Huang 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China; State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Shanghai Biomedical Co., Ltd. Zhangjiang, Pudong, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China; State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China; State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 4 State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; Shanghai Biomedical Co., Ltd. Zhangjiang, Pudong, Shanghai 201203, China.
  • 5 State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China; State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: tangfeng2013@simm.ac.cn.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China; State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; Shanghai Biomedical Co., Ltd. Zhangjiang, Pudong, Shanghai 201203, China. Electronic address: huangwei@simm.ac.cn.
PMID: 38981219 DOI: 10.1016/j.bmc.2024.117828
Abstract

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast Cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl Auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

Keywords

Affinity-directed conjugation; Antibody-drug conjugate (ADC); Glycoengineering; Site-specific; TROP2.

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