Abstract 89: A first-in-class humanized antibody fragment targeting platelet glycoprotein Ibα: a comprehensive preclinical study of CA1001 for the treatment of acute ischemic stroke

• DOI: 10.1161/str.56.suppl_1.89
• Publication Date: 2025-01-30T10:33:28Z
• Authors: Xiaohong Xu; Xi Lei; Guangheng Zhu; Zhenze Liu; Xudong Hu; Sladjana Slavkovic; Miguel Neves; Wenjing Ma; Huifang Xie; Preeti Preeti; Ruoying Yu; Hamed Shaykhalishahi; Cheng Zhang; Chuanbin Shen; Bei Li; Naping Tang; Yan Chang; Qian Xiang; Yimin Cui; Heyu Ni
• Keywords: Stroke; P-glycoprotein

Introduction: Platelet glycoprotein (GP) Ibα is a key receptor for thrombosis. Under high shear conditions, GPIbα-VWF interactions are required initiating platelet adhesion and vessel occlusion. GPIbα also an important checkpoint thrombo-inflammation in acute ischemic stroke. It has been considered as desirable target against stroke decades, but no anti-GPIbα drug successfully developed. Methods: CA1001 was humanized from our unique mAb crossing different species, manufactured under GMP-like conditions with 99.9% purity. The efficacy of assessed using various vitro functional assays blood samples vivo models, including state-of-the-art intravital microscopy thrombosis transient middle cerebral artery occlusion (tMCAO) models. Pharmacokinetics (PK), pharmacodynamics (PD), 14-day regulatory toxicology study were conducted rats rhesus monkeys. Results: specifically recognized human, monkeys, rats, mice, rabbits dogs. Using platelets healthy volunteers, patients peripheral disease, dose-dependently inhibited ristocetin-induced aggregation . laser injury FeCl 3 thrombosis, prevented occlusion, importantly, promoted thrombus dissolution (thrombolysis) In 60-min tMCAO intravenous injection 1 hour after significantly reduced the infarct volume at 24 hours without increasing risk intracerebral hemorrhage. PD studies showed that single bolus reached maximal anti-platelet effects within 5 minutes (0.25mg/kg 4mg/kg monkeys) which maintained following infusion. extent duration effect dose-dependent. Plasma concentrations increased linearly dose received. studies, well tolerated safe bleeding nor count reduction. No Obvious Adverse Event Level monkeys 25mg/kg, 100mg/kg respectively, 10 25 times therapeutic targeted doses. Conclusion: first-in-class Fab potent anti-thrombotic effects, consistent PK/PD properties favorable safety tolerability profiles warranting further clinical development volunteers