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Updated: Feb 2, 2026

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

Bo Wang1, Qiangzhe Zhang2, Yuqing Yang1

  • 1Department of Cell Biology, School of Medicine, Nankai University, Tianjin 300071, PR China.

Pharmacological Research
|January 31, 2026
PubMed

Insights

This study introduces novel probody-drug conjugates (PDCs) that precisely target ovarian cancer by activating in the tumor microenvironment. This new approach enhances tumor inhibition and reduces systemic toxicity compared to traditional antibody-drug conjugates.

Area of Science:

  • Oncology
  • Biotechnology
  • Drug Delivery

Background:

  • Traditional antibody-drug conjugates (ADCs) face challenges with on-target, off-tumor toxicities due to antigen expression on healthy cells.
  • Existing probodies often have narrow therapeutic indices because of tumor heterogeneity and non-specific payload conjugation.

Purpose of the Study:

  • To develop novel probody-drug conjugates (PDCs) targeting CD147 for improved ovarian cancer therapy.
  • To engineer PDCs with multiple protease-activated linkers for enhanced tumor specificity and reduced systemic toxicity.

Main Methods:

  • Generated anti-CD147 probodies using multiple-protease-activated linkers and epitope-derived masking peptides.
  • Site-specifically conjugated cytotoxic monomethyl auristatin E (MMAE) to create three probody-drug conjugates (PDCs).
  • Evaluated PDC activation by specific proteases (legumain, MMP-9, uPA) and assessed targeting potential and cytotoxicity in ovarian cancer models.

Main Results:

  • Developed three anti-CD147 PDCs activated by multiple proteases, exhibiting varied CD147-targeting potentials.
  • PDC1 demonstrated highly selective targeting and potent cytotoxicity against ovarian cancer cells.
  • PDC1 showed promising targeting selectivity and improved tumor inhibition in ovarian cancer xenograft models with no observed systemic toxicity.

Conclusions:

  • The developed multiple protease-activated, disulfide-bridging PDC strategy offers a precise and safe therapeutic approach for ovarian cancer.
  • This novel PDC design overcomes limitations of traditional ADCs, providing a potentially safer and more effective treatment option.
  • PDC1 represents a promising conditional antibody architecture for targeted ovarian cancer therapy.
Keywords:
Multiple protease-activation, Cluster of differentiation 147On-target off-tumor toxicityOvarian cancerProbody-drug conjugate

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