Structural basis for inhibition of βFXIIa by garadacimab

Abstract

FXIIa is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of Hereditary Angioedema (HAE). Here, we describe a high-resolution cryo-EM structure of the beta-chain from FXIIa ({beta}FXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to {beta}FXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This atypical structural mechanism is likely the primary contributor in the inhibition of activated FXII proteolytic activity in HAE. Garadacimab Fab-{beta}FXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXII. Structural analysis with other bonafide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a conserved mechanism of {beta}FXIIa inhibition, a novel finding of this study. In summary, garadacimab Fab-{beta}FXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. This work reaffirms the benefits of cryo-EM as a primary tool to study antigen-antibody complexes in near native state, particularly where other methods have fallen short.