9x1h
Cryo-EM Structure of human complement C1s CUB domain in complex with RAY121
Structural highlights
DiseaseC1S_HUMAN Defects in C1S are the cause of complement component C1s deficiency (C1SD) [MIM:613783. A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. FunctionC1S_HUMAN C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4. Publication Abstract from PubMedBACKGROUND: Antibody drugs blocking the complement classical pathway (CP) often require frequent intravenous administration to overcome the high abundance or rapid turnover of complement proteins. This makes treatment compliance burdensome for patients. METHODS: Screening was performed to identify anti-C1s antibodies specific for the CUB domain of C1s with CP neutralising function. Antibody engineering was performed on the anti-C1s antibody to prolong its half-life in circulation. The variable region was mutated to confer pH-dependent binding to C1s, and the antibody Fc was modified to lower its isoelectric point and to have enhanced binding to the neonatal Fc receptor. FINDINGS: A combination of pH-dependent binding to C1s and optimisation of charge characteristics was required for the final engineered antibody, RAY121, to achieve a long half-life in circulation and long-lasting neutralisation of the CP. In male cynomolgus monkeys, a single subcutaneous injection suppressed CP activity for more than a month. RAY121 neutralises the CP by using a unique mechanism of displacing C1q from the C1 complex and blocking its reassembly. Structure analysis by cryo-electron microscopy revealed that the RAY121 epitope on C1s is distinct from the C1q binding site, and that C1q displacement is mediated by the Fab arm sterically obstructing C1q binding to C1s. INTERPRETATION: RAY121 is able to neutralise the CP for an extended duration and is effective at doses that can be administered subcutaneously for convenient treatment. These data present RAY121 as a promising agent for the treatment of CP-driven autoimmune disorders. FUNDING: Chugai Pharmaceutical Co. Ltd. Long lasting complement neutralisation by RAY121, an engineered anti-C1s antibody with C1q displacement function.,Ho AWS, Fukuzawa T, Koga H, Ohmine K, Kawauchi H, Muraoka M, Ikuta Y, Gupta G, Okuda M, Onami I, Ayabe M, Takeiri A, Konishi H, Sugawara Y, Usami S, Ito E, Shibahara N, Ozeki K, Wada Y, Hirako A, Takahashi N, Sampei Z, Haraya K, Murao N, Fujii T, Torizawa T, Shimada H, Igawa T EBioMedicine. 2025 Nov 7;122:106009. doi: 10.1016/j.ebiom.2025.106009. PMID:41205294[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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