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<p>Despite advances in IgG-based cancer immunotherapy, challenges remain in effectively engaging innate immune responses against solid tumors. Here, IgA antibodies hold promise due to their ability to activate neutrophils and macrophages. We present a novel retargeted adenovirus-mediated approach that transforms cancer cells into “biofactories” for localized production of monomeric or dimeric IgA antibodies and a CD47 blocker to potentiate the effect of IgA antibodies. With our approach, tumor cells effectively produced IgA antibodies against tumor antigens such as EGFR or EpCAM and a soluble SIRPα-Fc fusion protein, which blocks the CD47-SIRPα axis. In a perfused tumor-on-a-chip model, locally produced IgA triggered neutrophil- and macrophage-mediated tumor cell killing, further potentiated by SIRPα-Fc co-production. In FcαRI-transgenic, tumor-bearing mice, intratumoral adenoviral injection induced strong local IgA and SIRPα-Fc expression, immune cell infiltration, and more than 50% tumor volume reduction after a single treatment. We found that dimeric IgA exerts stronger effects than monomeric IgA. Together, these results demonstrate that adenovirus-mediated, tumor-restricted delivery of IgA antibodies and CD47 blockade effectively engages innate immune mechanisms and has therapeutic promise.</p>

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Retargeted adenoviruses for local IgA and CD47 blocker production as a novel cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Mariya Chernyavska,
  • K Patricia Hartmann,
  • J H Marco Jansen,
  • Niklas Baumann,
  • Jonas Kolibius,
  • Dominik Brücher,
  • Theodora Kristoforus,
  • Rens H W Peters,
  • Lucas Huijs,
  • Daphne Laarveld,
  • Fabian Weiss,
  • Renate Burger,
  • Marta Lustig,
  • Nadine Gimenez de Assis,
  • Markus Schmid,
  • Jeanette H W Leusen,
  • Thomas Valerius,
  • Andreas Plückthun,
  • Wouter P R Verdurmen

摘要

Despite advances in IgG-based cancer immunotherapy, challenges remain in effectively engaging innate immune responses against solid tumors. Here, IgA antibodies hold promise due to their ability to activate neutrophils and macrophages. We present a novel retargeted adenovirus-mediated approach that transforms cancer cells into “biofactories” for localized production of monomeric or dimeric IgA antibodies and a CD47 blocker to potentiate the effect of IgA antibodies. With our approach, tumor cells effectively produced IgA antibodies against tumor antigens such as EGFR or EpCAM and a soluble SIRPα-Fc fusion protein, which blocks the CD47-SIRPα axis. In a perfused tumor-on-a-chip model, locally produced IgA triggered neutrophil- and macrophage-mediated tumor cell killing, further potentiated by SIRPα-Fc co-production. In FcαRI-transgenic, tumor-bearing mice, intratumoral adenoviral injection induced strong local IgA and SIRPα-Fc expression, immune cell infiltration, and more than 50% tumor volume reduction after a single treatment. We found that dimeric IgA exerts stronger effects than monomeric IgA. Together, these results demonstrate that adenovirus-mediated, tumor-restricted delivery of IgA antibodies and CD47 blockade effectively engages innate immune mechanisms and has therapeutic promise.