Structural and functional characterization of a specific antidote for ticagrelor

Area of Science:

• Cardiovascular Pharmacology
• Drug Development
• Hemostasis and Thrombosis

Background:

• Ticagrelor is a P2Y12 antagonist used for acute coronary syndrome, but increases bleeding risk.
• An antidote is needed to manage ticagrelor-associated bleeding, especially during emergencies.

Purpose of the Study:

• To identify and characterize a specific antidote for ticagrelor.
• To evaluate the antidote's efficacy in neutralizing ticagrelor's antiplatelet activity and reversing bleeding.

Main Methods:

• Identification and in vitro/in vivo pharmacology of a ticagrelor-specific antigen-binding fragment (Fab).
• Assessed Fab affinity, specificity, neutralization of free ticagrelor, and reversal of antiplatelet effects.
• Evaluated antidote efficacy in a mouse model of ticagrelor-induced bleeding during acute surgery.

Main Results:

• The Fab antidote demonstrated high affinity (20 pM) and specificity for ticagrelor, not binding related compounds.
• The antidote effectively neutralized ticagrelor and reversed its antiplatelet activity in vitro and in vivo.
• The Fab antidote normalized bleeding in a surgical mouse model.

Conclusions:

• A specific Fab antidote for ticagrelor has been developed.
• This antidote effectively reverses ticagrelor's pharmacological effects and associated bleeding.
• It holds potential value for managing patients requiring emergency procedures while on ticagrelor therapy.