{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:44:06Z","timestamp":1782751446692,"version":"3.54.5"},"reference-count":27,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-dose intravenous immunoglobulin (IVIG) is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the fragment crystallizable (Fc) portion. Further, recent data indicate that recombinant multimeric Fc molecules exhibit potent anti-inflammatory properties. In this study, we investigated the biochemical and biological properties of different recombinant human IgG1 Fc molecules with increasing valency and avidity, combined with mutations to increase binding affinity to complement protein C1q. These molecules were investigated for their potential dual antagonism: to antagonize Fc\u03b3 receptor (Fc\u03b3R) effector functions (Ab-dependent cellular phagocytosis) in vitro, and to inhibit the activation of the classical complement pathway. C1q-binding mutants demonstrated an exponential increase in potency to inhibit the classical pathway in correlation with increasing multimerization. Importantly, in contrast to other multimeric Fc constructs such as Fc hexamers, no generation of complement C4a was observed. Reducing the binding affinity to Fc\u03b3RIIB resulted in a half-life extension of the trivalent hIgG1-Fc molecules in human neonatal Fc receptor transgenic (hFcRn Tg) mice. Our data demonstrate a potent anti-inflammatory effect of recombinant human IgG1-Fc C1q-binding mutants in vitro and in vivo, mediated by blockade of Fc\u03b3Rs and inhibition of complement activation.<\/jats:p>","DOI":"10.3390\/cells15131156","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:37:55Z","timestamp":1782391075000},"page":"1156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Trivalent Human IgG1-Fc Proteins for Potent Complement Inhibition"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3731-966X","authenticated-orcid":false,"given":"Ian K.","family":"Campbell","sequence":"first","affiliation":[{"name":"CSL Limited, Bio21 Institute, 30 Flemington Rd., Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Momenta Pharmaceuticals Inc., Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Bosques","sequence":"additional","affiliation":[{"name":"Momenta Pharmaceuticals Inc., Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1953-2018","authenticated-orcid":false,"given":"Matthew P.","family":"Hardy","sequence":"additional","affiliation":[{"name":"CSL Limited, Bio21 Institute, 30 Flemington Rd., Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Tester","sequence":"additional","affiliation":[{"name":"CSL Limited, Bio21 Institute, 30 Flemington Rd., Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Tomasetig","sequence":"additional","affiliation":[{"name":"CSL Limited, Bio21 Institute, 30 Flemington Rd., Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0223-1497","authenticated-orcid":false,"given":"Daniel","family":"Couto","sequence":"additional","affiliation":[{"name":"CSL Behring Biologics Research Center, Swiss Institute for Translational and Entrepreneurial Medicine, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9470-9877","authenticated-orcid":false,"given":"Thomas","family":"Gentinetta","sequence":"additional","affiliation":[{"name":"CSL Behring Biologics Research Center, Swiss Institute for Translational and Entrepreneurial Medicine, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-1915","authenticated-orcid":false,"given":"Sabine","family":"Pestel","sequence":"additional","affiliation":[{"name":"CSL Behring GmbH, 35041 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6941-8796","authenticated-orcid":false,"given":"Padmapriya","family":"Ponnuswamy","sequence":"additional","affiliation":[{"name":"CSL Behring GmbH, 35041 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4255-9350","authenticated-orcid":false,"given":"Fabian","family":"K\u00e4sermann","sequence":"additional","affiliation":[{"name":"CSL Behring Biologics Research Center, Swiss Institute for Translational and Entrepreneurial Medicine, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Spirig","sequence":"additional","affiliation":[{"name":"CSL Behring Biologics Research Center, Swiss Institute for Translational and Entrepreneurial Medicine, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102366","DOI":"10.1016\/j.autrev.2019.102366","article-title":"Next-Generation Fc Receptor\u2013Targeting Biologics for Autoimmune Diseases","volume":"18","author":"Zuercher","year":"2019","journal-title":"Autoimmun. 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