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Antibody Targeted Against P2Y 12 Receptor Reduces Platelet Activity In vitro and In vivo
Author(s) -
Hensch Nicole R,
Karim Zubair A,
Khasawneh Fadi T
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.943.9
Subject(s) - platelet , platelet activation , in vivo , receptor , p2y receptor , chemistry , pharmacology , medicine , immunology , biochemistry , biology , purinergic receptor , microbiology and biotechnology
Platelet hyperactivity is known to give rise to thrombotic disorders, and many antiplatelet therapies are designed to reduce the risk of thrombogenesis. ADP is an important platelet activator and activates platelets by binding to the P2Y 1 receptor or P2Y 12 receptor, both of which are G‐coupled protein receptors located on the platelets’ surface. To this end, although the involvement of the P2Y 12 platelet receptor in thrombosis is well characterized, there are currently no parenteral drugs targeting these receptors in clinical use to complement existing antiplatelet therapies. In this study, we designed a parenteral agent, namely an antibody targeted against the P2Y 12 receptor ligand biding domain (abbreviated as P2Y 12 Ab). In vitro studies revealed that the addition of P2Y 12 Ab could effectively inhibit aggregation induced by ADP. P2Y 12 Ab was also found to inhibit aggregation activated by U46619 and thrombin. Using FACS analysis, reduced P selectin and Annexin V exposure and reduced integrin activation was also evident in the presence of P2Y 12 Ab. As for its in vivo activity, the P2Y 12 Ab also demonstrated inhibitory effects in a FeCl 3 ‐induced thrombosis model, producing a prolonged occlusion time; however, a lengthened bleeding time was also observed. Overall, our findings suggest that P2Y 12 Ab functionally blocks platelet activity, further indicating that the P2Y 12 platelet receptor plays a central role in thrombogenesis. These studies also validate the use of P2Y 12 Ab as a purposed parenteral antiplatelet agent to be implemented in conjunction with or as an alternative to current antiplatelet strategies. Support or Funding Information This research was supported by funds provided by College of Pharmacy, Western University of Health Sciences (to F.T.K).