HDX-MS study on garadacimab binding to activated FXII reveals potential binding interfaces through differential solvent exposure. Issue 1 (31st December 2023)

• Record Type: Journal Article
• Authors: Ow, Saw Yen; Kapp, Eugene A.; Tomasetig, Vesna; Zalewski, Anton; Simmonds, Jason; Panousis, Con; Wilson, Michael J.; Nash, Andrew D.; Pelzing, Matthias
• Is Part Of: MAbs. Volume 15:Issue 1(2023)
• Publication Date: 2023-12-31
• Subjects: HDX-MS -- binding stoichiometry -- epitope mapping -- Hageman factor -- negative stain electron microscopy -- SPR; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2022.2163459
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Hageman factor (FXII) is an essential component in the intrinsic coagulation cascade and a therapeutic target for the prophylactic treatment of hereditary angioedema (HAE). CSL312 (garadacimab) is a novel high-affinity human antibody capable of blocking activated FXII activity that is currently undergoing Phase 3 clinical trials in HAE. Structural studies using hydrogen/deuterium exchange coupled to mass spectrometry revealed evidence of interaction between the antibody and regions surrounding the S1 specificity pocket of FXII, including the 99-loop, 140-loop, 180-loop, and neighboring regions. We propose complementarity-determining regions (CDRs) in heavy-chain CDR2 and CDR3 as potential paratopes on garadacimab, and the 99-loop, 140-loop, 180-loop, and 220-loop as binding sites on the beta chain of activated FXII (β-FXIIa).