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<p>Trophoblast cell surface antigen 2 (TROP2), a transmembrane glycoprotein highly expressed in a variety of epithelial cancers, has been considered as a primary therapeutic target for the development of antibody–drug conjugates (ADCs). OBI-992, an investigational TROP2-targeted ADC, is composed of a novel TROP2 antibody (R4702) conjugated to the topoisomerase I (TOP1) inhibitor exatecan through a hydrophilic enzyme-cleavable linker. This study aimed to characterize R4702 and OBI-992 in vitro. TROP2-targeted antibodies sacituzumab and datopotamab were employed as the comparators for R4702. ADCs sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) were used as benchmarks for OBI-992. Results revealed that R4702 binds to an epitope that is distinct from sacituzumab and datopotamab. The cytotoxicity of the OBI-992, SG, and Dato-DXd against different cancer cells is comparable despite they have different internalization profile. Upregulation of breast cancer resistance protein (BCRP) was observed in SG-resistant and Dato-DXd-resistant cells, but not in OBI-992-resistant cells. In addition, significant downregulation of TROP2 expression was detected with Dato-DXd-resistant cells and only slightly downregulation with SG- and OBI-992-resistant cells was observed. Moreover, substantial enhancement of cytotoxicity and DNA damage was found in the combination of OBI-992 with a poly (ADP-ribose) polymerase (PARP) inhibitor (talazoparib). Taken together, the findings in this study support further clinical development of OBI-992.</p>

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Preclinical evaluation of a novel antibody–drug conjugate OBI-992 for Cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Ting-Yu Chang,
  • Chun-Jung Lin,
  • Shih-Ni Wen,
  • Yi-Chen Wu,
  • Cheng-Yen Wei,
  • Jye-Yu Huang,
  • Yu-Hsuan Tsao,
  • Yu-Jung Chen,
  • Wei-Chien Tang,
  • Yuen-Chin Wu,
  • Wei-Han Lee,
  • Teng-Yi Huang,
  • Tzer-Min Kuo,
  • Wan-Fen Li,
  • Ming-Tain Lai

摘要

Trophoblast cell surface antigen 2 (TROP2), a transmembrane glycoprotein highly expressed in a variety of epithelial cancers, has been considered as a primary therapeutic target for the development of antibody–drug conjugates (ADCs). OBI-992, an investigational TROP2-targeted ADC, is composed of a novel TROP2 antibody (R4702) conjugated to the topoisomerase I (TOP1) inhibitor exatecan through a hydrophilic enzyme-cleavable linker. This study aimed to characterize R4702 and OBI-992 in vitro. TROP2-targeted antibodies sacituzumab and datopotamab were employed as the comparators for R4702. ADCs sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) were used as benchmarks for OBI-992. Results revealed that R4702 binds to an epitope that is distinct from sacituzumab and datopotamab. The cytotoxicity of the OBI-992, SG, and Dato-DXd against different cancer cells is comparable despite they have different internalization profile. Upregulation of breast cancer resistance protein (BCRP) was observed in SG-resistant and Dato-DXd-resistant cells, but not in OBI-992-resistant cells. In addition, significant downregulation of TROP2 expression was detected with Dato-DXd-resistant cells and only slightly downregulation with SG- and OBI-992-resistant cells was observed. Moreover, substantial enhancement of cytotoxicity and DNA damage was found in the combination of OBI-992 with a poly (ADP-ribose) polymerase (PARP) inhibitor (talazoparib). Taken together, the findings in this study support further clinical development of OBI-992.