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Here, we repurpose the native IgG Fc\u2013Fc\u03b3R 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\u2013Fc\u03b3R complex forms a homodimeric Fc with one ligand, with the Fc\u03b3R 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 Fc\u03b3RIIIa (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.<\/jats:p>","DOI":"10.1038\/s41467-026-72425-5","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:01:58Z","timestamp":1777370518000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generation of mixed-valency, modular multispecific antibodies using disulfide-linked Fc\u2013Fc\u03b3R complexes"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9914-4351","authenticated-orcid":false,"given":"Miso","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Ly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-8071","authenticated-orcid":false,"given":"Bea","family":"Parcutela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeran","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmina","family":"Ladra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asaul","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yead","family":"Jewel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjun","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Valerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4075-2544","authenticated-orcid":false,"given":"Timothy W.","family":"Synold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-0861","authenticated-orcid":false,"given":"Le Xuan Truong","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-5908","authenticated-orcid":false,"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0522-384X","authenticated-orcid":false,"given":"John C.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"72425_CR1","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1016\/j.cell.2022.05.029","volume":"185","author":"PJ Carter","year":"2022","unstructured":"Carter, P. 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The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5821"}}