Improved Highly Potent Specific Human Kunitz Inhibitor of Fibrinolytic Enzyme Plasmin
Tech ID: 30531 / UC Case 2019-981-0
SUMMARY
UCLA researchers in the School of Medicine have developed mutant polypeptides of the tissue factor pathway inhibitor-2 (TFPI-2) Kunitz domain 1 (KD1), which can serve as potent inhibitors of fibrinolysis.
BACKGROUND
Fibrinolysis, an important biological process involving the degradation of fibrin clots, is primarily controlled by the enzyme plasmin. However, hyperfibrinolysis leading to excessive bleeding is a frequent complication of many medical procedures, including cardiac bypass surgery, combat wounds, thrombolytic therapy, organ transplantation, and orthopedic surgery. Currently used antifibrinolytic agents lack high affinity and specificity, necessitating high doses which can lead to side effects and organ toxicity. Aprotinin (Bovine pancreatic trypsin inhibitor), a very strong and effective drug in inhibiting plasmin, was withdrawn from the market because of its inhibition of kallikrein, a major side effect. Therefore, there is a strong need for more effective and safer antifibrinolytic agents.
INNOVATION
UCLA researchers have generated mutant polypeptides based on human TFPI-2 KD1, a known inhibitor of plasmin. The experimental binding data suggest that some mutants exhibit improvements over the wild type KD1 in both plasmin inhibition and clotting strength intensification. Furthermore, in vivo studies in mice indicate that the mutant polypeptides outperform wild type KD1 and current antifibrinolytic agents in inhibiting plasmin and reducing blood loss. Notably, the KD1 mutants are very poor inhibitors of kallikrein and extremely strong inhibitors of plasmin. Importantly, the mutants show no renal toxicity and do not lead to immune reactions in mice.
APPLICATIONS
Cardiac Bypass Surgery
Antifibrinolysis/plasmin inhibition
Anti-cancer treatment
Protease inhibition
ADVANTAGES
Higher antifibrinolytic activity
No renal toxicity
Low immunogenicity
STATE OF DEVELOPMENT
This invention has been developed and tested in mice.
RELATED MATERIALS
Bajaj, M. S. et al. "Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis Properties of KD1-L17R Variant". J. Biol. Chem. 2011, 286, 4329–4340.
PATENT STATUS
Country Type Number Dated Case
United States Of America Issued Patent 8,993,719 03/31/2015 2006-064
United States Of America Published Application 20140288000 09/25/2014 2012-611