{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:47:15Z","timestamp":1782535635134,"version":"3.54.5"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A therapeutic antibody, CSL305, has been developed, which combines inhibition of the complement classical and lectin pathways via complement C2 binding with an ability to act as an antagonist of the neonatal Fc receptor (FcRn). CSL305 binds to human C2 (huC2) but shows no binding or activity against mouse C2 precluding its use in mouse models of disease to fully assess in vivo efficacy. To circumvent this, a mouse strain was developed that replaced the expression of mouse C2 with huC2 by homologous recombination. These mice (huC2 \u201cknock-in\u201d; KI) were shown to express huC2 protein and to have complement activity. Interestingly, male huC2-KI mice showed much stronger complement activity compared to female mice and were also sensitive to inhibition by CSL305. Two models of disease using male huC2-KI mice were then used to assess the in vivo efficacy of CSL305. The first was an attenuated passive anti-glomerular basement membrane (GBM) glomerulonephritis model involving complement activation as its primary mechanism of action. CSL305 showed dose-dependent inhibition of disease as measured by urine albumin, with reductions in kidney cellular infiltration and plasma C3 cleaved fragments C3b\/C3c\/iC3b also observed. The second model was a collagen autoantibody-induced arthritis (CAIA) mouse model. Here, CSL305 showed a significant and dose-dependent inhibition of clinical score in both prophylactic and therapeutic settings, mediated exclusively via its FcRn mechanism of action. Although the animal models used in this study were found to preclude the demonstration of a synergistic effect on both mechanisms, CSL305 does act in vivo as both a complement inhibitor and as a FcRn antagonist to ameliorate disease.<\/jats:p>","DOI":"10.3390\/ijms27125525","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:37:42Z","timestamp":1781879862000},"page":"5525","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vivo Efficacy of an Inhibitor of Complement and FcRn in Models of Glomerulonephritis and Collagen-Induced Arthritis Using Human C2 Knock-In Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Helen","family":"Cao","sequence":"first","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Nash","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Dai","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Hsu","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Turner","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaushala","family":"Jayawardana","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Vyas","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Barr","sequence":"additional","affiliation":[{"name":"CSL Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Wymann","sequence":"additional","affiliation":[{"name":"CSL Biologics Research Centre, Swiss Institute for Translational and Entrepreneurial Medicine, 3010 Bern, Switzerland"}],"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 Ltd., Bio21 Institute, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00011-025-02061-0","article-title":"The complement system in autoimmune diseases: Pathogenesis, diagnostic markers, and therapeutic strategies","volume":"74","author":"Gao","year":"2025","journal-title":"Inflamm. 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