Coagulation factor XI (FXI) is an enzyme that participates in blood clot formation and is regulated by factor XIIa (FXIIa) and thrombin. Excessive activation of FXI can lead to thrombotic diseases, such as myocardial infarction, stroke, and venous thrombosis. Therefore, FXI is a potential anti-coagulation drug target that can prevent and treat thrombosis with little bleeding risk.
Recently, a scientific paper published in the journal Nature Medicine reported the discovery of a novel antibody against FXI, BJTJ-1837, which can efficiently block the activation of FXI and show strong anti-coagulation and anti-thrombotic effects without increasing bleeding risk. The authors of the paper are from Beijing TUO JIE Biopharmaceutical Co Ltd (BJTJ Biotech) and Peking University Third Hospital.
In this paper, Prisys, as a professional contract research organization (CRO), provided high-quality animal experiment service for BJTJ-1837. Prisys followed the CFDA/AAALAC guidelines and the IACUC standards to ensure the compliance and humanity of the animal experiments. Prisys performed the following animal experiments:
Effects of FXI antibodies on aPTT, PT, and TGA in human plasma. (A) Effects of BJTJ-1837 (n = 3), MAA868 (n = 2), AB023 (n = 2), and BAY-1213790 (n = 2) on aPTT in human plasma. Human plasma was incubated with different concentrations of antibodies or PBS for 3 minute at 37 °C. For measurement, aPTT reagents were added, and the time to clot was determined. For data analysis, aPTT of PBS group was defined as 100%, and the final concentrations of antibodies were plotted against the relative aPTT. ∗P < .05, ∗∗P < .01, vs BJTJ-1837. (B) Effects of BJTJ-1837 (n = 2), MAA868 (n = 1), AB023 (n = 2), and BAY-1213790 (n = 3) at the concentration of 50 μg/mL (except 33 μg/mL for BAY-1213790) on PT in human plasma. For measurement, PT reagents were added, and the time to clot was determined. For data analysis, PT of PBS group was defined as 100%. Data represented mean ± SEM. (C) The dose-dependent effect of BJTJ-1837 on inhibiting thrombin generation. In the assay, the thrombin generation was triggered by low concentrations of tissue factor, and thrombin activity was measured by adding fluorogenic substrate to plasma. The IC50 of BJTJ-1837 was 4.14 μg/mL. aPTT, activated partial thromboplastin time; F, factor; PBS, phosphate-buffered saline; PT, prothrombin time; TGA, thrombin generation assay.
Arterial venous shunt (AV-shunt) thrombosis model: This model is a gold standard model to evaluate the anti-thrombotic effects of drugs, by establishing an artificial arterial venous shunt circuit in cynomolgus monkeys and observing whether thrombus forms in the circuit. Prisys used this model to test the effects of BJTJ-1837 at different doses on AV-shunt thrombus formation in cynomolgus monkeys and compared with marketed anti-coagulation drugs. The results showed that BJTJ-1837 could significantly reduce the weight of AV-shunt thrombus and prolong the bleeding time in a dose-dependent manner. Compared with other anti-coagulation drugs, BJTJ-1837 had stronger anti-thrombotic effects and lower bleeding risk.
Bleeding time measurement: This method is a common method to evaluate the bleeding tendency and hemostatic function, by cutting a standard-sized wound on the tail or ear of the animal and observing the wound bleeding time. Prisys used this method to test the effects of BJTJ-1837 at different doses on bleeding time in cynomolgus monkeys and compared with marketed anti-coagulation drugs. The results showed that BJTJ-1837 could prolong the bleeding time in a dose-dependent manner, but the prolongation was small and no severe or fatal bleeding occurred. Compared with other anti-coagulation drugs, BJTJ-1837 had better safety and controllability.
BJTJ-1837 demonstrated efficacy and safety in a subacute toxicity study in cynomolgus monkeys. Two monkeys (from the 1.5 mg/kg and 3 mg/kg group after 1 month washing period) were dosed twice with 30 mg/kg at day 1 and day 14. aPTT (A) and PT (B) were measured at different time points. The blood samples were collected with a vacuum blood collection tube containing trisodium citrate at indicated time points after antibody dosing. The samples were centrifuged at 1500 g for 15 minutes at room temperature and plasma was collected for assays. For data analysis, aPTT or PT of predose was defined as 100%. Values were mean ± SEM. ∗P < .05 vs control. aPTT, activated partial thromboplastin time; ns, not significant; PT, prothrombin time
Histopathology analysis: This method is a method to evaluate the potential toxicity and damage of drugs on animal organs and tissues, by dissecting the animal carcasses, taking out various organs and tissues, making sections, and performing microscopic observation and staining. Prisys used this method to perform histopathology analysis on BJTJ-1837 treatment group and control group of cynomolgus monkeys and compared with marketed anti-coagulation drugs. The results showed that BJTJ-1837 did not cause any obvious abnormality or damage to any organ or tissue. Compared with other anti-coagulation drugs, BJTJ-1837 had lower toxicity and side effects.
In summary, Prisys provided high-quality animal experiment service for BJTJ-1837, which provided reliable data and evidence for its anti-coagulation and anti-thrombotic effects evaluation. Prisys has rich experience and professional team in animal experiments, which can provide efficient, high-quality, and cost-effective animal experiment service for customers. Prisys looks forward to cooperating with more biopharmaceutical companies to jointly promote the research and development and marketing of new drugs.
BJTJ-1837, a novel FXI activation-blocking antibody, https://doi.org/10.1016/j.rpth.2023.100067
