A recombinant signalling‐selective activated protein C that lacks anticoagulant activity is efficacious and safe in cutaneous wound preclinical models

• Published in: Wound repair and regeneration Vol. 32; no. 1; pp. 90 - 103
• Main Authors: Zhao, Ruilong, Xue, Meilang, Lin, Haiyan, Smith, Margaret, Liang, Helena, Weiler, Hartmut, Griffin, John H., Jackson, Christopher J.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.01.2024
• Subjects: 3K3A‐APC; activated protein C (APC); animal model; Animals; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; cell culture; Endothelial Cells - metabolism; Female; Fibrinolytic Agents - therapeutic use; Humans; Mice; Protein C - metabolism; Protein C - pharmacology; Protein C - therapeutic use; Swine; Wound Healing; 3K3A-APC; wound healing; activated protein C (APC); animal model; cell culture
• ISSN: 1067-1927; 1524-475X; 1524-475X
• DOI: 10.1111/wrr.13148

Various preclinical and clinical studies have demonstrated the robust wound healing capacity of the natural anticoagulant activated protein C (APC). A bioengineered APC variant designated 3K3A‐APC retains APC's cytoprotective cell signalling actions with <10% anticoagulant activity. This study was aimed to provide preclinical evidence that 3K3A‐APC is efficacious and safe as a wound healing agent. 3K3A‐APC, like wild‐type APC, demonstrated positive effects on proliferation of human skin cells (keratinocytes, endothelial cells and fibroblasts). Similarly it also increased matrix metollaproteinase‐2 activation in keratinocytes and fibroblasts. Topical 3K3A‐APC treatment at 10 or 30 μg both accelerated mouse wound healing when culled on Day 11. And at 10 μg, it was superior to APC and had half the dermal wound gape compared to control. Further testing was conducted in excisional porcine wounds due to their congruence to human skin. Here, 3K3A‐APC advanced macroscopic healing in a dose‐dependent manner (100, 250 and 500 μg) when culled on Day 21. This was histologically corroborated by greater collagen maturity, suggesting more advanced remodelling. A non‐interference arm of this study found no evidence that topical 3K3A‐APC caused either any significant systemic side‐effects or any significant leakage into the circulation. However the female pigs exhibited transient and mild local reactions after treatments in week three, which did not impact healing. Overall these preclinical studies support the hypothesis that 3K3A‐APC merits future human wound studies.