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
  • 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: [email protected].
  • 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: [email protected].
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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