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<p>Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its high expression on SCLC but limited expression on normal tissues. Here, we developed a bispecific T cell engager, IAR025, and investigated its antitumor efficacy against SCLC. IAR025 has a CD3 arm for T cell activation and a DLL3 arm for recognizing tumor cells with optimal affinity and binding domain. IAR025 resulted in a dose-dependent eradication of DLL3-positive SCLC cells, without nonspecific cell destruction in DLL3-negative cells in vitro. Administration of IAR025 in DMS79 and SHP-77 humanized mouse models significantly inhibited tumor growth. The mechanism study revealed that IAR025 treatment led to increased T-cell recruitment in tumors. IAR025 activity was further enhanced when combined with chemotherapy or anti-PD-1 treatment. In cynomolgus monkeys, IAR025 was well-tolerated at a dose up to 10&#xa0;mg/kg and exhibited linear pharmacokinetics with a half-life of 90&#xa0;h. Collectively, these preclinical results demonstrate that IAR025 is a highly potent therapeutic strategy for treating SCLC.</p>

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IAR025, a novel anti-DLL3 x CD3-bispecific antibody, displays high antitumor efficacy in preclinical models of small-cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Yang Liu,
  • Lei Cao,
  • Mengqiu Xu,
  • Ninghuan Li,
  • Jian Zhang,
  • Mengjia Zhu,
  • Zhihui Kuang,
  • Huijun Sha,
  • Min Wu,
  • Jinling Xu,
  • Zhihai Wu,
  • Ye Feng,
  • Li Li

摘要

Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its high expression on SCLC but limited expression on normal tissues. Here, we developed a bispecific T cell engager, IAR025, and investigated its antitumor efficacy against SCLC. IAR025 has a CD3 arm for T cell activation and a DLL3 arm for recognizing tumor cells with optimal affinity and binding domain. IAR025 resulted in a dose-dependent eradication of DLL3-positive SCLC cells, without nonspecific cell destruction in DLL3-negative cells in vitro. Administration of IAR025 in DMS79 and SHP-77 humanized mouse models significantly inhibited tumor growth. The mechanism study revealed that IAR025 treatment led to increased T-cell recruitment in tumors. IAR025 activity was further enhanced when combined with chemotherapy or anti-PD-1 treatment. In cynomolgus monkeys, IAR025 was well-tolerated at a dose up to 10 mg/kg and exhibited linear pharmacokinetics with a half-life of 90 h. Collectively, these preclinical results demonstrate that IAR025 is a highly potent therapeutic strategy for treating SCLC.