{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:48:23Z","timestamp":1789069703224,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chugai Pharmaceutical Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris\u00ae) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris\u00ae), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky\u00ae), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5\u2013crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab\u2019s distinctive molecular features, showing its eliminated binding to Fc\u03b3 receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients\u2019 quality of life.<\/jats:p>","DOI":"10.3390\/ijms252111679","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T06:55:37Z","timestamp":1730357737000},"page":"11679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Beyond Recycling Antibodies: Crovalimab\u2019s Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-4468","authenticated-orcid":false,"given":"Zenjiro","family":"Sampei","sequence":"first","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"},{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9142-5607","authenticated-orcid":false,"given":"Kenta","family":"Haraya","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"},{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6982-4492","authenticated-orcid":false,"given":"Siok Wan","family":"Gan","sequence":"additional","affiliation":[{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-9785","authenticated-orcid":false,"given":"Masaru","family":"Muraoka","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"},{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Hayasaka","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Fukuzawa","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"},{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiri","family":"Shida-Kawazoe","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"},{"name":"Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8608-4393","authenticated-orcid":false,"given":"Akihiko","family":"Gotoh","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoshi","family":"Obara","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-1013","authenticated-orcid":false,"given":"Yasutaka","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/ejh.13166","article-title":"Diagnosis and management of PNH: Review and recommendations from a Belgian expert panel","volume":"101","author":"Devos","year":"2018","journal-title":"Eur. 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