title: Structural and functional characterization of a specific antidote for ticagrelor.
abstract: Ticagrelor is a direct-acting reversibly binding P2Y12 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, P2Y12. Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 5'-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.
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Andrew
authors: A
authors: Buchanan
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Philip
authors: P
authors: Newton
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Susanne
authors: S
authors: Pehrsson
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Tord
authors: T
authors: Inghardt
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Thomas
authors: T
authors: Antonsson
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Peder
authors: P
authors: Svensson
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Tove
authors: T
authors: Sjögren
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Linda
authors: L
authors: Öster
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Annika
authors: A
authors: Janefeldt
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Ann-Sofie
authors: AS
authors: Sandinge
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Feenagh
authors: F
authors: Keyes
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Mark
authors: M
authors: Austin
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Jennifer
authors: J
authors: Spooner
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Peter
authors: P
authors: Gennemark
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Mark
authors: M
authors: Penney
authors: AstraZeneca Global Medicines Development, Gaithersburg, MD.
authors: Garnet
authors: G
authors: Howells
authors: MedImmune R&D, Cambridge, United Kingdom;
authors: Tristan
authors: T
authors: Vaughan
authors: AstraZeneca R&D Mölndal, Mölndal, Sweden; and.
authors: Sven
authors: S
authors: Nylander
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000302:isolation & purification / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000494:pharmacology*; D000918:Antibody Specificity; D000931:Antidotes / Q000737:chemistry* / Q000494:pharmacology*; D000080908:Broadly Neutralizing Antibodies; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D015202:Protein Engineering; D000077486:Ticagrelor / Q000037:antagonists & inhibitors
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D000931:Antidotes; D000080908:Broadly Neutralizing Antibodies; D007140:Immunoglobulin Fab Fragments; C000622443:PB-2452; D000077486:Ticagrelor; D000241:Adenosine