Glenzocimab: A GPVI (Glycoprotein VI)-Targeted Potential Antiplatelet Agent for the Treatment of Acute Ischemic Stroke

Abstract

It has previously been shown in several animal experiments that platelet GPVI (glycoprotein VI) contributes to thrombosis, particularly in ischemic stroke. Moreover, GPVI levels are upregulated in stroke patients. This review describes the therapeutic roles of anti-GPVI antibody in preclinical models of ischemic stroke and provides the current evidence for potential benefits of glenzocimab, a Fab fragment of humanized anti-GPVI monoclonal antibody, in stroke patients. Anti-GPVI antibody, JAQ1, significantly decreased infarct volume and improved neurological function in mice with transient middle cerebral artery occlusion, a model of ischemic stroke, with no or minor bleeding tendency. Intravenous injection of glenzocimab in nonhuman primates produced rapid inhibition of ex vivo platelet aggregation induced by collagen (a GPVI ligand). Complete platelet inhibition is observed at 30 minutes following administration without increasing the risk of bleeding. In humans, glenzocimab is well tolerated and produces dose-dependent antiplatelet activity. More importantly, glenzocimab (125–1000 mg) was safe when administered as soon as possible (<3 hours) following reperfusion with the r-tPA (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke. Although glenzocimab 1000 mg (a selected dose) did not demonstrate a significant improvement in overall clinical outcomes, it appeared to provide benefits in severe cases and in patients who required thrombectomy. This promising efficacy together with a good safety profile of glenzocimab warrant further investigation in phase III (ACTISAVE [Adaptive Efficacy and Safety Study of Glenzocimab Used as an Add-On Therapy on Top of Standard of Care in the 4.5 Hours Following an Acute Ischemic Stroke]) clinical study.

Spatial Proteomics Analysis of Soft and Stiff Regions in Human Acute Arterial Thrombus

“…22 Platelets might interact with collagen through their receptors with GP (glycoprotein) Ib/V/IX as previously reported. 23 Whether targeting GP Ib/V/ IX can prevent platelet activation in the stiff regions of the thrombus and change the composition of the thrombus await future study. In addition, platelet activation promotes inflammation which contributes to the interaction of platelets with endothelial cells and neutrophils.…”

Platelet–Neutrophil Crosstalk in Thrombosis

“…The inflammatory involvement of platelets in stroke is thought to be mediated via GPVI, as well as the VWF A1-GPIbα axis, but not α IIb β 3 [ 72 , 73 , 74 ]. In line with this, recent clinical trials with GPVI antagonists showed promising outcomes in the treatment of acute ischemic stroke [ 75 , 76 , 77 ]. Neutrophils were detected within hours of stroke onset and their numbers correlated with the infarct size in humans and mice [ 78 , 79 , 80 ].…”

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

“…To emphasize rapid interventions, which help prevent neuronal loss during ischemic stroke, the phrase “time is brain” is widely used . Nevertheless, the success rate for complete re-canalization following intravenous thrombolytic therapy is less than 50%, suggesting the need for novel therapeutic agents . A genetic study reported that the CG/GG genotypes of the FURIN rs2071410 SNP are associated with ∼50% increased risk of transient ischemic attack (TIA), compared with the homozygous CC genotype (Table ).…”

“…129 Nevertheless, the success rate for complete re-canalization following intravenous thrombolytic therapy is less than 50%, suggesting the need for novel therapeutic agents. 130 A genetic study reported that the CG/ GG genotypes of the FURIN rs2071410 SNP are associated with ∼50% increased risk of transient ischemic attack (TIA), compared with the homozygous CC genotype (Table 2). 95 This SNP potentially contributes to a reduction in furin activity and an increase in hypertension, 35 a strong associated risk factor of TIA.…”