178 Ganjiang East Road，Suzhou, Jiangsu The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, China (People's Republic)
Background: Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia.
Aims: We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody HAPC1573 that selectively blocks the anticoagulant activity of human activated protein C (APC) to improve bleeding tendency in hemophilia.
Methods: We used Affinity maturation and molecular characterization and Antibody-binding kinetics analysis by SPR to prepare monoclonal antibodies with higher affinity for APC and then validated the hemostatic and cytoprotective effects of SR604 in a hemophilia model and cytoprotective effects in an inflammatory state, as well as its safety under high-dose conditions, by using a mouse tail-cutting, knee injury model, LPS-induced inflammation model and monkey acute toxicity assay.
Results: SR604 effectively blocked the anticoagulation activities of APC in various human coagulation factor-deficient plasma in vitro with affinities approximately 60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail bleeding and knee injury models of hemophilia A and B mice expressing human APC (humanized hemophilia mice). SR604 did not interfere with the cyto-protection and endothelial barrier function of APC nor have obvious toxicity effects in humanized hemophilia mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneous injection of SR604 in cynomolgus monkeys.
Conclusion(s): These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.
