Pharmacological Profile of JNJ-64179375: A Novel, Long-Acting Exosite-1 Thrombin Inhibitor
| Autor: | Qiu Li, Madhu Chintala, Fuyong Du, Eilyn R. Lacy, Matthew Bunce, Zheng Huang Devine |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Blood Platelets
Male 0301 basic medicine Pharmacology Thrombin time Antithrombins Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Thrombin In vivo medicine Animals Humans Prothrombin time Dose-Response Relationship Drug medicine.diagnostic_test Chemistry Antibodies Monoclonal Recombinant Proteins Thromboelastography Rats Macaca fascicularis 030104 developmental biology Mechanism of action Immunoglobulin G Molecular Medicine medicine.symptom Ecarin clotting time Platelet Aggregation Inhibitors 030217 neurology & neurosurgery Protein Binding circulatory and respiratory physiology medicine.drug Partial thromboplastin time |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 371:375-384 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.119.261032 |
| Popis: | JNJ-64179375 (abbreviated as JNJ-9375) is a recombinant human immunoglobin G4 (IgG4) monoclonal antibody engineered to mimic an immunoglobin A (IgA) antibody that was identified in a patient who exhibited markedly prolonged clotting times but without spontaneous bleeding episodes over several years of follow-up. The crystal structure of the JNJ-9375 Fab-thrombin complex showed an almost identical binding mode to that of the patient IgA. In the current study, we characterized the in vitro and in vivo properties of JNJ-9375. Surface plasmon resonance studies demonstrated that JNJ-9375 binds to alpha-thrombin with high affinity and specificity (KD: 0.8nM for human thrombin). JNJ-9375 produced dose-dependent prolongation of in vitro clotting assays in human plasma, including thrombin time (TT), ecarin clotting time (ECT), prothrombin time (PT), and activated partial thromboplastin time (aPTT), with EC2X of 4.4, 12.4, 172.6, and 202.7µg/ml, respectively. JNJ-9375 inhibited thrombin induced platelet aggregation in human plasma with an IC50 of 52.6 nM (7.8 µg/ml) and produced a dose-dependent prolongation of reaction time tested by thromboelastography. JNJ-9375 pretreatment resulted in dose-dependent reduction in thrombus formation in the rat arteriovenous shunt model of thrombosis. Robust efficacy was observed at 0.3mg/kg accompanied by a 1.5x of TT. Bleeding was increased at 3 mg/kg in a rat tail transection bleeding model demonstrating a therapeutic index of 10X compared to 1X for apixaban in the same models. Our data suggests that thrombin exosite I inhibition is efficacious against thrombosis in a pretreatment prevention animal model. SIGNIFICANCE STATEMENT JNJ-9375 is a novel, fully human monoclonal antibody that binds to the exosite I region of thrombin with high affinity and specificity. JNJ-9375 dose dependently prolonged clotting times and inhibited thrombin induced platelet aggregation in in vitro assays based on its mechanism of action. In an in vivo rat AV shunt model, JNJ-9375 prevented thrombus formation in a dose dependent fashion while demonstrated reduced bleeding risk. The present study demonstrated the anti-thrombotic effects of inhibiting the exosite I region of thrombin when given in a prevention mode in preclinical animal models. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|