Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI

J Mol Biol. 2019 Dec 6;431(24):4817-4833. doi: 10.1016/j.jmb.2019.09.008. Epub 2019 Oct 24.


Factor XI (FXI), the zymogen of activated FXI (FXIa), is an attractive target for novel anticoagulants because FXI inhibition offers the potential to reduce thrombosis risk while minimizing the risk of bleeding. BAY 1213790, a novel anti-FXIa antibody, was generated using phage display technology. Crystal structure analysis of the FXIa-BAY 1213790 complex demonstrated that the tyrosine-rich complementarity-determining region 3 loop of the heavy chain of BAY 1213790 penetrated deepest into the FXIa binding epitope, forming a network of favorable interactions including a direct hydrogen bond from Tyr102 to the Gln451 sidechain (2.9 Å). The newly discovered binding epitope caused a structural rearrangement of the FXIa active site, revealing a novel allosteric mechanism of FXIa inhibition by BAY 1213790. BAY 1213790 specifically inhibited FXIa with a binding affinity of 2.4 nM, and in human plasma, prolonged activated partial thromboplastin time and inhibited thrombin generation in a concentration-dependent manner.

Keywords: Allosteric mechanism; Anticoagulant; Binding epitope; Phage display; X-ray structure.

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Antibodies, Monoclonal, Humanized / chemistry*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / pharmacology
  • Blood Coagulation
  • Catalysis
  • Epitopes / chemistry
  • Factor XIa / antagonists & inhibitors
  • Factor XIa / chemistry*
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Structure-Activity Relationship
  • Thrombelastography
  • Thrombin / metabolism


  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Epitopes
  • Immunoglobulin Fab Fragments
  • Factor XIa
  • Thrombin
  • osocimab