Two Birds, One Stone: Anti-β3 Integrin PSI Domain Antibodies Inhibit Both Platelet Aggregation and Blood Coagulation
ISTH Academy. Neves M. Jul 10, 2019; 273921; OC 78.4 Topic: Platelet Antagonists & Novel Therapeutics
Miguel Neves
Miguel Neves
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OC 78.4

Two Birds, One Stone: Anti-β3 Integrin PSI Domain Antibodies Inhibit Both Platelet Aggregation and Blood Coagulation

T.W. Stratton1, M. Neves1,2, G. Zhu1, Y. Wang1,2, P. Chen1,2, R.C. Gallant1, P.A.A. Norris1, J. Freedman1, H. Ni1,2
1St. Michael's Hospital / University of Toronto, Toronto, Canada, 2Canadian Blood Services Centre for Innovation, Toronto, Canada

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: Integrin αIIbβ3 plays key roles in thrombosis and hemostasis through mediating platelet adhesion and aggregation. We recently reported the active site of thiol-isomerases, CXXC, is expressed twice within the plexin-semaphorin-integrin (PSI) domain across all integrins (Blood, 2017). We developed anti-β3 integrin PSI domain monoclonal antibodies (mAbs) that inhibit the thiol-isomerase activity of β3 PSI domain and decrease platelet adhesion, aggregation, and thrombosis without increasing bleeding. Interestingly, the mAbs inhibition of thrombosis in vivo was 10-20x greater than on in vitro platelet aggregation.
Aims: Mechanistically explore how the PSI domain contributes to blood coagulation.
Methods: Utilize our proprietary anti-β3 PSI domain mAbs in in vitro / ex vivo coagulation assays.
Results: Clot retraction assays performed with human and mouse blood showed less clot retraction and a significantly lower dry clot weight in whole blood treated with anti-PSI mAbs compared to controls. Laser scanning confocal microscopy of platelet-rich plasma (PRP) samples with labelled fibrin(ogen) showed that fibrin network formation of anti-PSI mAb treated clots was significantly decreased. To measure blood coagulation, thromboelastography (TEG) was performed. Blinded TEG showed that coagulation decreased in anti-PSI mAb-treated whole blood (human and mouse) and PRP. We further compared our anti-PSI mAbs with other anti-β3 integrin mAbs. TEG analysis uncovered that the anti-PSI mAbs significantly decreased coagulation parameters, much more than M1, JAN D1, and the Abciximab precursor 7E3, which more potently inhibit αIIbβ3-fibrinogen binding and platelet aggregation. This suggests the decreased coagulation may result from the anti-thiol-isomerase activity of the anti-PSI mAbs and its impact on coagulation factors. The mechanistic features of this inhibitory effect are under investigation.
Conclusions: This is the first evidence of an allosteric therapeutic target of β3 integrin and suggests that targeting the PSI domain partially blocks platelet aggregation and coagulation, resulting in less bleeding while maintaining strong anti-thrombotic effects.

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