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Leon Campbell Professorship"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    The Fc region of therapeutic IgG antibodies is often engineered to remove or \u201csilence\u201d Fc effector functions, but it remains unclear whether these mutations eliminate all Fc-mediated effector activity. Human Fc receptor-like 5 (FCRL5\/FcRH5) is a low-affinity IgG Fc receptor expressed on B cells and is an actively pursued antibody target in multiple myeloma. Here, we show that common Fc function-silencing mutations do not impair FCRL5-mediated activity and therefore attenuate, rather than eliminate, Fc effector function. The crystal structure of the FCRL5-IgG1 Fc complex, solved at 3.4 \u00c5 resolution, revealed that FCRL5 binds IgG1 Fc in a 1:1 complex through a binding mode distinct from that of classical Fc\u03b3 receptors, explaining why mutations that attenuate Fc effector function spare FCRL5 binding. Fc-engineered antibodies that selectively engage FCRL5 inhibited B cell receptor-induced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    flux in FCRL5-expressing B cells. These findings demonstrate that Fc-attenuated therapeutic IgG retains the ability to engage FCRL5, identifying an unappreciated pathway for B cell modulation.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aei1233","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:58:31Z","timestamp":1787939911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Structure-function analysis of the FCRL5\u2013IgG1 Fc complex reveals an unappreciated pathway for B cell modulation by Fc-attenuated IgG"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6771-4810","authenticated-orcid":true,"given":"Bart M.","family":"Herpers","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9103-975X","authenticated-orcid":true,"given":"Mo","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghwan","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-9476","authenticated-orcid":true,"given":"George","family":"Delidakis","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-3292","authenticated-orcid":true,"given":"Jin Eyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7156-4423","authenticated-orcid":true,"given":"Chang-Han","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed I.","family":"Gadallah","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-0217","authenticated-orcid":true,"given":"Jennifer S.","family":"Brodbelt","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9360-5388","authenticated-orcid":true,"given":"Y. 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