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Background <p>Bispecific antibodies that redirect T cells or NK cells to tumors have demonstrated substantial therapeutic efficacy, but their broader application is often constrained by immune-related toxicities, limited effector cell availability, and suboptimal access to tumor sites. These challenges have prompted efforts to identify alternative effector cell types that are more abundant in circulation, readily accessible, and capable of cytotoxic activity in the tumor microenvironment. Neutrophils, which constitute the most prevalent circulating leukocyte population, represent a promising yet underutilized target for immune cell engager design. However, efforts to exploit neutrophil-mediated tumor killing through CD89 (FcαRI) have been limited by the inherent drawbacks of IgA-based formats, including poor stability, short serum half-life, and reduced developability.</p> Results <p>To address these challenges, we established an engineered bispecific antibody platform that incorporates CD89 engagement into an IgG1 scaffold. This design enables neutrophil redirection while preserving the favorable pharmacokinetic and manufacturing profiles of IgG-based therapeutics. The resulting bispecific architecture allows for programmable neutrophil engagement alongside tumor antigen recognition, offering a clinically viable strategy for innate immune activation. Among the bispecific designs evaluated, ZT-8, a humanized CD89 × HER2 bispecific antibody, demonstrated potent neutrophil-mediated cytotoxicity against tumor cells even in the absence of cytokine priming, suggesting a distinct activation mechanism that operates within the tumor microenvironment. Compared to IgA-based antibodies, ZT-8 exhibited superior immune effector engagement, enhanced tumoricidal activity, and substantially prolonged in vivo half-life through FcRn-mediated recycling.</p> Conclusion <p>These findings define IgG-based CD89 bispecifics as a next-generation neutrophil engager platform and exemplify how antibody engineering and synthetic immunology can be leveraged to expand the effector landscape of bispecific immunotherapies.</p>

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Engineered neutrophil engagers overcome IgA limitations and reprogram resting neutrophils for cancer immunotherapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月5日

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  • Jisun Lee,
  • Garam Han,
  • Munsu Kyung,
  • Seunghyeon Lee,
  • Tae Woo Kim,
  • Sang Taek Jung

摘要

Background

Bispecific antibodies that redirect T cells or NK cells to tumors have demonstrated substantial therapeutic efficacy, but their broader application is often constrained by immune-related toxicities, limited effector cell availability, and suboptimal access to tumor sites. These challenges have prompted efforts to identify alternative effector cell types that are more abundant in circulation, readily accessible, and capable of cytotoxic activity in the tumor microenvironment. Neutrophils, which constitute the most prevalent circulating leukocyte population, represent a promising yet underutilized target for immune cell engager design. However, efforts to exploit neutrophil-mediated tumor killing through CD89 (FcαRI) have been limited by the inherent drawbacks of IgA-based formats, including poor stability, short serum half-life, and reduced developability.

Results

To address these challenges, we established an engineered bispecific antibody platform that incorporates CD89 engagement into an IgG1 scaffold. This design enables neutrophil redirection while preserving the favorable pharmacokinetic and manufacturing profiles of IgG-based therapeutics. The resulting bispecific architecture allows for programmable neutrophil engagement alongside tumor antigen recognition, offering a clinically viable strategy for innate immune activation. Among the bispecific designs evaluated, ZT-8, a humanized CD89 × HER2 bispecific antibody, demonstrated potent neutrophil-mediated cytotoxicity against tumor cells even in the absence of cytokine priming, suggesting a distinct activation mechanism that operates within the tumor microenvironment. Compared to IgA-based antibodies, ZT-8 exhibited superior immune effector engagement, enhanced tumoricidal activity, and substantially prolonged in vivo half-life through FcRn-mediated recycling.

Conclusion

These findings define IgG-based CD89 bispecifics as a next-generation neutrophil engager platform and exemplify how antibody engineering and synthetic immunology can be leveraged to expand the effector landscape of bispecific immunotherapies.