mAbs (Dec 2023)

A HER2-targeted antibody-novel DNA topoisomerase I inhibitor conjugate induces durable adaptive antitumor immunity by activating dendritic cells

  • Xiaoding Tan,
  • Peng Fang,
  • Kaiying Li,
  • Meng You,
  • Yuxia Cao,
  • Hui Xu,
  • Xiaohong Zhu,
  • Lu Wang,
  • Xin Wei,
  • Haiying Wen,
  • Wendi Li,
  • Lei Shi,
  • Xiaowei Sun,
  • Dongan Yu,
  • Huikai Zhu,
  • Zhenzhen Wang,
  • Datao Liu,
  • Hui Shen,
  • Wei Zhou,
  • Maomao An

DOI
https://doi.org/10.1080/19420862.2023.2220466
Journal volume & issue
Vol. 15, no. 1

Abstract

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ABSTRACTWe designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6’s ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody–drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.

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