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<p>There is a strong need for multispecific antibodies that possess favorable clinical properties and can be generated through a simple and efficient process. Here, we repurpose the native IgG Fc–FcγR interaction into a universal, covalent docking site using only a single engineered disulfide bond, providing a simple solution to bypass the complex, bespoke engineering typically required for multispecific antibody design. The resulting Fc–FcγR complex forms a homodimeric Fc with one ligand, with the FcγR offering both N- and C-termini for independent functionalization, enabling single- or dual-payload formats, including masked designs for conditional activation. Introducing the disulfide between Fc (A330C) and FcγRIIIa (I106C) yields stable, covalently linked complexes that do not require post-expression modification, are compatible with standard mammalian expression, and support payloads such as anti-CD3, anti-CD28, IL-2, and protease-activated IL-2. These compounds exhibit potent, antigen-selective cytotoxicity in vitro and in vivo, with tunable avidity and reduced off-target activity. This plug-and-play platform overcomes key developability bottlenecks and enables rapid, scalable creation of next-generation antibody therapeutics.</p>

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Generation of mixed-valency, modular multispecific antibodies using disulfide-linked Fc–FcγR complexes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月28日

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  • Miso Park,
  • Kevin Ly,
  • Bea Parcutela,
  • Hyeran Choi,
  • Carmina Ladra,
  • Asaul Gonzalez,
  • Yead Jewel,
  • Hyunjun Kang,
  • Melissa Valerio,
  • Aparna Krishnan,
  • Timothy W. Synold,
  • Le Xuan Truong Nguyen,
  • Guido Marcucci,
  • John C. Williams

摘要

There is a strong need for multispecific antibodies that possess favorable clinical properties and can be generated through a simple and efficient process. Here, we repurpose the native IgG Fc–FcγR interaction into a universal, covalent docking site using only a single engineered disulfide bond, providing a simple solution to bypass the complex, bespoke engineering typically required for multispecific antibody design. The resulting Fc–FcγR complex forms a homodimeric Fc with one ligand, with the FcγR offering both N- and C-termini for independent functionalization, enabling single- or dual-payload formats, including masked designs for conditional activation. Introducing the disulfide between Fc (A330C) and FcγRIIIa (I106C) yields stable, covalently linked complexes that do not require post-expression modification, are compatible with standard mammalian expression, and support payloads such as anti-CD3, anti-CD28, IL-2, and protease-activated IL-2. These compounds exhibit potent, antigen-selective cytotoxicity in vitro and in vivo, with tunable avidity and reduced off-target activity. This plug-and-play platform overcomes key developability bottlenecks and enables rapid, scalable creation of next-generation antibody therapeutics.