GPVI/​Glenzocimab
In brief

DISCOVERY OF A NEW AND PROMISING TARGET

the Platelet Glycoprotein VI (GPVI)

GPVI is a platelet membrane protein that belongs to the immunoglobulin superfamily.GPVI is expressed exclusively by platelets and their precursors, megakaryocytes. GPVI is a key receptor on platelets for polymerized fibrin, fibrinogen and collagen1. GPVI interaction with its ligands triggers platelet activation leading to aggregation and the recruitment of additional platelets, and promotes coagulation2. GPVI blockade has demonstrated efficient antithrombotic potential in experimental models of thrombosis, without increasing bleeding3.

GPVI deficiency does not provoke bleeding. It contributes to protecting mice from thrombosis in different models. Patients with a genetic deficiency in GPVI usually do not bleed.

Targeting GPVI is an attractive antithrombotic strategy without the apparent risk of bleeding complications.4

Glenzocimab story

Rooted in pioneering academic research

The development of glenzocimab is rooted in pioneering academic research carried out at INSERM demonstrating that a specific mouse monoclonal antibody fragment (9O12) targeting human platelet GPVI exerted antithrombotic properties without inducing an additional bleeding risk5.

Acticor Biotech then designed and selected a humanized monoclonal antibody fragment (ACT017), later named glenzocimab, with high affinity and selectivity for GPVI6.

Glenzocimab binds specifically to human platelets and disrupts the interaction between GPVI and its major ligands: polymerized fibrin, fibrinogen and collagen. It blocks GPVI-triggered platelet activation in vitro and ex vivo, and the intravenous administration of glenzocimab is antithrombotic in animal models and does not induce bleeding5.

In a placebo-controlled phase 1 clinical trial in Healthy Volunteers, glenzocimab proved to be safe and well tolerated, with no Safety Adverse Events (SAE), dose or time-related adverse events being reported, and no prolongation of bleeding time7. Its pharmacokinetic/pharmacodynamic properties were characterized and this enabled the definition of doses and dosing regimens for clinical studies of glenzocimab8 in patients.

Sources

[1] Mammadova-Bach, E. et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 126, 683–691 (2015).

[2] Jandrot-Perrus, M. et al. Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Blood 96, 1798–1807 (2000).

[3] Jiang, P. & Jandrot-Perrus, M. New advances in treating thrombotic diseases: GPVI as a platelet drug target. Drug Discov. Today 19, 1471–1475 (2014).

[4] Denorme, F. & Rondina, M. T. Targeting glycoprotein VI for thromboembolic disorders. Arterioscler. Thromb. Vasc. Biol. 39, 839–840 (2019).

[5] Jiang, P. & Jandrot-Perrus, M. New advances in treating thrombotic diseases: GPVI as a platelet drug target. Drug Discov. Today 19, 1471–1475 (2014).

[6] Lebozec, K., Jandrot-Perrus, M., Avenard, G., Favre-Bulle, O. & Billiald, P. Design, development and characterization of ACT017, a humanized Fab that blocks platelet’s glycoprotein VI function without causing bleeding risks. MAbs 9, 945–958 (2017).

[7] Voors-Pette, C. et al. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) fab. Arterioscler. Thromb. Vasc. Biol. 39, 956–964 (2019).

[8] Renaud, L. et al. Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation. J. Clin. Pharmacol. 60, 1198–1208 (2020).

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