{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:53:37Z","timestamp":1781106817581,"version":"3.54.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"13","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,31]]},"abstract":"<jats:p>\n                    Antigen-specific immunoglobulin-G (IgG) antibodies cause or contribute to the pathogenesis of a wide spectrum of human diseases and conditions. Multiple therapeutic approaches have been developed, yet they are limited by variable safety and efficacy, patient inconvenience, and cost. IdeS, a cysteine protease derived from\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">S. pyogenes<\/jats:italic>\n                    <\/jats:italic>\n                    , specifically cleaves IgG antibodies, representing a unique opportunity for the treatment of IgG-mediated diseases. However, clinical utilization of IdeS is limited by the immunogenic nature of bacterial proteases and short half-life. Using Seismic\u2019s IMPACT platform, we engineered S-1117, an IgG cleaving enzyme fused to a human effectorless IgG1 Fc domain for an extended half-life. S-1117 is being developed to address the limitations of existing therapies in IgG-mediated diseases. In vitro and in vivo pharmacology studies demonstrate that S-1117 exhibits reduced B and T cell immunogenicity, a superior pharmacokinetic profile, and manufacturability and developability properties resembling those of monoclonal antibodies. S-1117 cleavage of IgG reduces circulating levels of IgG, including pathogenic IgG autoantibodies and IgG immune-complexes, and reduces IgG antibody effector functions, such as complement fixation, antibody-dependent cellular cytotoxicity, and antibody-dependent cell phagocytosis. The polypharmacology of S-1117 further extends to cleaving the antigen receptor on IgG-positive memory B cells, thereby modulating activation of memory B cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2518366123","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:07:16Z","timestamp":1774462036000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Polypharmacology of S-1117, an Fc-fused IgG-selective degrading enzyme, for chronic treatment of autoantibody-mediated diseases"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0996-4953","authenticated-orcid":false,"given":"Liliana M.","family":"Sanmarco","sequence":"first","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Pellerin","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0911-1198","authenticated-orcid":false,"given":"Tobias","family":"Green","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin","family":"Plasencia","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6387-6590","authenticated-orcid":false,"given":"Jordan M.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam","family":"Le","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andita","family":"Newton","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6382-5606","authenticated-orcid":false,"given":"Jiyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Independent Consultant","place":["Moraga"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cecilia","family":"Ramello","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Peckner","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Manasson","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2080-6146","authenticated-orcid":false,"given":"Yi","family":"Xing","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0720-1191","authenticated-orcid":false,"given":"Heather","family":"Vital","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Higginson-Scott","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Sundy","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin L.","family":"Otipoby","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan D.","family":"Mascanfroni","sequence":"additional","affiliation":[{"name":"Seismic Therapeutic","place":["Watertown"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V50.2.317.317"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00720-1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00159-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1139\/m84-175"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.12.3046"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1607"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407965101"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.22930"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001692"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfq115"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.086470"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000003496"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16754"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1612567"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.70.2.101"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2853"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78084"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221662"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1143"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2022.2145997"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2024.103719"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-025-00708-2"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.05.023"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00309-0"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30378-2"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/ene.16189"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2505984122"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-017-0473-8"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03787-x"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm6020016"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.4.952"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61495-1"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2024.103719"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2110297"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19858"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2518366123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:08:25Z","timestamp":1774462105000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2518366123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":35,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,3,31]]}},"alternative-id":["10.1073\/pnas.2518366123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2518366123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"assertion":[{"value":"2025-07-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2518366123"}}