Safety and efficacy of anti-human activated protein C antibody SR604 for prophylaxis of congenital factor deficiencies.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. 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). 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 were there obvious toxicity effects in humanized hemophilia mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneous SR604 injection in cynomolgus monkeys. 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.