Platelet-targeted thromboprophylaxis with a human serum albumin fusion drug: Preventing thrombosis and reducing cardiac ischemia/reperfusion injurywithout bleeding complications

• Published in: Theranostics Vol. 14; no. 8; pp. 3267 - 3281
• Main Authors: Song, Yuyang, Bienvenu, Laura A, Bongcaron, Viktoria, Prijaya, Shania A, Maluenda, Ana C, Walsh, Aidan P G, McFayden, James D, Pietersz, Geoffrey A, Peter, Karlheinz, Wang, Xiaowei
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 2024
• Subjects: Animals; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Blood Platelets - drug effects; Blood Platelets - metabolism; Disease Models, Animal; Hemorrhage - prevention & control; Humans; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction - drug therapy; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - prevention & control; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Research Paper; Serum Albumin, Human; Single-Chain Antibodies - pharmacology; Single-Chain Antibodies - therapeutic use; Thrombosis - drug therapy; Thrombosis - prevention & control; targeted drug delivery; thrombosis; anticoagulant; antiplatelet; thromboprophylaxis
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.97517

Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI. However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding. We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation. This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications. Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition. A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP). Its efficacy was investigated using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury. Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition . Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice. By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration. Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin. Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups. Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. The inclusion of HSA represents a significant advancement in the design of targeted therapeutic agents for thromboprophylaxis. Our activated platelet-targeted targ-HSA-TAP is a highly effective antithrombotic drug with both anticoagulant and antiplatelet effects while retaining normal hemostasis. The long half-life of targ-HSA-TAP provides the unique opportunity to use this antithrombotic drug for more effective, long-lasting and safer anti-thrombotic prophylaxis. In cases where MI occurs, this prophylactic strategy reduces thrombus burden and effectively reduces cardiac I/R injury.