Structural and functional characterization of a specific antidote for ticagrelor

Abstract

• In the clinic, all oral antiplatelet medicines have a risk of bleeding complications.• We present an antidote for ticagrelor that reverses its antiplatelet effect in human platelet-rich plasma and its bleeding effect in mice.Ticagrelor is a direct-acting reversibly binding P2Y 12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y 12 . Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 59-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures. (Blood. 2015;125(22):3484-3490)

Restoring Platelet Function in Patients on P2Y 12 Receptor Inhibitor Treatment

“…As an antigen-binding fragment (Fab) antidote, it successfully neutralized ticagrelor and ticagrelor's active metabolite in a preclinical study. 12 Importantly, the antidote also normalized ticagrelor-dependent bleeding in a mouse model of acute surgery. 12 Interestingly, the affinity of the Fab antidote is ≈100 times stronger than the affinity of ticagrelor for its target receptor, which may at least, in part, explain the convincing results reported to date.…”

“…12 Importantly, the antidote also normalized ticagrelor-dependent bleeding in a mouse model of acute surgery. 12 Interestingly, the affinity of the Fab antidote is ≈100 times stronger than the affinity of ticagrelor for its target receptor, which may at least, in part, explain the convincing results reported to date. Although published result 12 is promising for this agent, further preclinical and clinical investigations are necessary and ongoing.…”

“…5 However, in interpreting the data, some issues and important aspects merit mentioning: First, in APTITUDE, various platelet function profiles were used as surrogate end points to assess the pharmacological characteristics of the currently available oral P2Y 12 receptor inhibitors in a setting of platelet transfusion for platelet function restoration. Although platelet function markers for this study were wisely chosen, the interplay of blood platelets, various signaling cascades, and the entire coagulation system to achieve hemostasis is complex and can hardly be explored entirely by ex vivo testing.…”

“…Contrary, this well-recognized ischemic benefit of DAPT is cut down by an increased on-treatment bleeding risk including major and fatal bleeding in both a nonoperative and operative setting like coronary artery bypass grafting (CABG). 2,3 Bleeding risks differ for the currently available oral P2Y 12 receptor inhibitors. On the basis of the results of large-scale clinical trials and the clinical experience in recent years, we considered that the risk of bleeding to be modest for the second-generation thienopyridine clopidogrel, whereas more potent platelet inhibition, such as it is delivered by the third-generation thienopyridine prasugrel or the cyclo-pentyl-triazolo-pyrimidine ticagrelor, comes along with a substantially higher risk of bleeding.…”

“…ual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is the current mainstay of pharmacological treatment in both patients with stable coronary artery disease and acute coronary syndrome managed invasively by percutaneous coronary intervention (PCI). 1 The primary goal of DAPT is to reduce the risk of ischemic events including (re)-infarction and stent thrombosis.…”