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<p>Antibody-drug conjugates (ADCs) are constrained by limited tumor penetration of IgG formats and heterogeneity from stochastic conjugation. We addressed these challenges by engineering a compact trastuzumab Fab-based ADC with site-specific installation of DM1 using the peptide ligase butelase-1 and by extending serum persistence via genetic fusion of an albumin-binding domain (ABD). Butelase-1 ligation proceeded rapidly under mild conditions to afford a homogeneous product with a defined drug-to-antibody ratio. The conjugate selectively killed HER2-positive cells in vitro while sparing HER2-negative controls. ABD fusion increased serum albumin binding and improved in vivo exposure; the resulting T-Fab-ABD(H + L)-DM1 produced superior tumor growth inhibition in HER2-positive xenografts compared with its non-ABD analogue. The ADC showed no significant body weight loss or organ damage in mice, indicating good tolerability. These findings validate a modular strategy combining a Fab scaffold, enzymatic site-specific conjugation, and ABD-mediated half-life extension to generate potent, homogeneous ADCs and nominate T-Fab-ABD(H + L)-DM1 as a promising candidate for HER2-positive cancer therapy.</p>

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Site-specific trastuzumab Fab-DM1 via butelase-1 with ABD fusion for potent HER2-positive tumor control

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Yiming Han,
  • Qi Guo,
  • Han Cao,
  • Tingwei Qin,
  • Xiudian Zhang,
  • Qisheng Dong,
  • Yibo Huang,
  • Yifeng Mao,
  • Ziteng Wang,
  • Quanyong Liu,
  • Yangxue Liu,
  • Shoutao Zhang

摘要

Antibody-drug conjugates (ADCs) are constrained by limited tumor penetration of IgG formats and heterogeneity from stochastic conjugation. We addressed these challenges by engineering a compact trastuzumab Fab-based ADC with site-specific installation of DM1 using the peptide ligase butelase-1 and by extending serum persistence via genetic fusion of an albumin-binding domain (ABD). Butelase-1 ligation proceeded rapidly under mild conditions to afford a homogeneous product with a defined drug-to-antibody ratio. The conjugate selectively killed HER2-positive cells in vitro while sparing HER2-negative controls. ABD fusion increased serum albumin binding and improved in vivo exposure; the resulting T-Fab-ABD(H + L)-DM1 produced superior tumor growth inhibition in HER2-positive xenografts compared with its non-ABD analogue. The ADC showed no significant body weight loss or organ damage in mice, indicating good tolerability. These findings validate a modular strategy combining a Fab scaffold, enzymatic site-specific conjugation, and ABD-mediated half-life extension to generate potent, homogeneous ADCs and nominate T-Fab-ABD(H + L)-DM1 as a promising candidate for HER2-positive cancer therapy.