Factor XII/XIIa inhibitors: Their discovery, development, and potential indications

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• Coagulation factor XII (FXII), a serine protease, has recently revealed its complex roles in coagulation, immunity, and the kallikrein-kinin system.
• Its inhibition is a therapeutic target for hereditary angioedema and thrombosis associated with artificial surfaces.

Purpose of the Study:

• To review the discovery and development of FXII inhibitors.
• To discuss their potential therapeutic indications, including hereditary angioedema and neuro-inflammatory disorders.

Main Methods:

• Review of scientific literature on FXII and its inhibitors.
• Analysis of current clinical development of FXII-targeting therapies, such as garadacimab.
• Identification of various inhibitor classes, including peptides, proteins, antibodies, and RNA-based technologies.

Main Results:

• FXII plays a crucial role at the crossroads of coagulation, immune response, and kinin-kallikrein systems.
• Inhibitors derived from natural sources (arthropods, plants) and biotechnological methods are advancing.
• Garadacimab, an anti-FXII antibody, is in Phase II clinical trials for hereditary angioedema.

Conclusions:

• FXII inhibition represents a significant therapeutic avenue for hereditary angioedema and potentially other conditions.
• Ongoing research into FXII's role in neuroinflammation may unveil new treatment strategies.
• Diverse FXII inhibitor platforms are being explored for broad clinical utility.