2. Academic Validation
  3. Multiple protease-activated probody-drug conjugates for treating CD147-positive ovarian cancer with limited toxicity

Multiple protease-activated probody-drug conjugates for treating CD147-positive ovarian cancer with limited toxicity

  • Pharmacol Res. 2026 Mar:225:108120. doi: 10.1016/j.phrs.2026.108120.
Bo Wang 1,  Qiangzhe Zhang 2,  Yuqing Yang 1,  Chenhui Wang 1,  Guiyu Deng 3,  Ying Chen 4,  Zichang Xu 5,  Zhinan Chen 6,  Chuanzheng Zhou 7,  Sihe Zhang 8
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Medicine, Nankai University, Tianjin 300071, PR China.
  • 2 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China; Department of Oncology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, PR China.
  • 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
  • 4 Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
  • 5 School of Intelligent Biomedical Engineering, Hunan University of Technology and Business, Changsha, Hunan 410205, PR China.
  • 6 Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China.
  • 7 State Key Laboratory of Elemento-Organic Chemistry, Department of Chemical Biology, College of Chemistry, Nankai University Tianjin, 300071, PR China.
  • 8 Department of Cell Biology, School of Medicine, Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].
PMID: 41620149 DOI: 10.1016/j.phrs.2026.108120
Abstract

Traditional antibody-drug conjugates (ADCs) that target antigens expressed not only on tumor cells but also on nonmalignant cells are often associated with unavoidable on-target off-tumor toxicities. Probodies are masked antibody prodrugs that remain inactive until proteolytically activated in the tumor microenvironment (TME). However, most probodies are produced on the basis of a monoresponsive design and achieve a narrow therapeutic index owing to tumor heterogeneity and nonspecific payload-conjugation. Here, we generated different probodies targeting the cluster of differentiation 147 (CD147) antigen based on the design of multiple-protease-activated linker peptide and HcHAb18 antibody epitope-derived masking peptides. Three anti-CD147 probody-drug conjugates (PDCs) were produced via site-specific conjugation with cytotoxic monomethyl Auristatin E (MMAE) through mild cysteine-selective chemical reactions. The created probodies and PDCs can be activated through cleavage by the proteases Legumain, matrix-metalloproteinases 9, and urokinase-type plasminogen activator, but exhibit different CD147-targeting potentials. Importantly, PDC1, one of the conditional antibody architectures, exhibits highly selective targeting and strongest cytotoxicity to ovarian Cancer cells. More importantly, PDC1 demonstrated promising targeting selectivity and improved the tumor-inhibition efficiency in ovarian cancer-xenograft mouse models without systemic toxicity. This multiple protease-activated, disulfide-bridging PDC strategy provides a novel, precise and safe ADC-targeted therapeutics against ovarian Cancer.

Keywords

Multiple protease-activation, Cluster of differentiation 147; On-target off-tumor toxicity; Ovarian cancer; Probody-drug conjugate.

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