Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent

• Published in: Structure (London) Vol. 26; no. 2; pp. 187 - 198.e4
• Main Authors: Ely, Lauren K., Lolicato, Marco, David, Tovo, Lowe, Kate, Kim, Yun Cheol, Samuel, Dharmaraj, Bessette, Paul, Garcia, Jorge L., Mikita, Thomas, Minor, Daniel L., Coughlin, Shaun R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 06.02.2018; Elsevier
• Subjects: active-site inhibitor; Animals; Antibodies, Monoclonal - metabolism; anticoagulant; Anticoagulants; Binding Sites, Antibody; coagulation; crystal structure; factor XI; Factor XIa - metabolism; hemostasis; Humans; IgG; intrinsic pathway; protease inhibitor; protease-blocking antibody; Protein Conformation; thrombosis; Thrombosis - metabolism; protease-blocking antibody; protease inhibitor; factor XI; thrombosis; intrinsic pathway; IgG; crystal structure; anticoagulant; hemostasis; active-site inhibitor; coagulation
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2017.12.010

Coagulation factor XIa is a candidate target for anticoagulants that better separate antithrombotic efficacy from bleeding risk. We report a co-crystal structure of the FXIa protease domain with DEF, a human monoclonal antibody that blocks FXIa function and prevents thrombosis in animal models without detectable increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and active site, while the heavy chain provides electrostatic interactions with the surface of FXIa. The structure accounts for the specificity of DEF for FXIa over its zymogen and related proteases, its active-site-dependent binding, and its ability to inhibit substrate cleavage. The inactive FXIa protease domain used to obtain the DEF-FXIa crystal structure reversed anticoagulant activity of DEF in plasma and in vivo and the activity of a small-molecule FXIa active-site inhibitor in vitro. DEF and this reversal agent for FXIa active-site inhibitors may help support clinical development of FXIa-targeting anticoagulants. [Display omitted] •Anticoagulants that better separate prevention of thrombosis and bleeding are needed•DEF, an mAb to FXIa, prevents thrombosis without detectable bleeding in animals•DEF is highly specific for FXIa over its zymogen and other coagulation proteases•A DEF-FXIa structure explains DEF activity and specificity and provides an antidote Inhibition of coagulation factor XI (FXI) may prevent thrombosis with less bleeding. DEF is a human monoclonal antibody that blocks the active form of FXI (FXIa). Ely et al. describe a structure that explains the anticoagulant function and specificity of DEF for FXIa and identifies an antidote for FXIa inhibitors.