An Agonistic Monoclonal Antibody Targeting cMet Attenuates Inflammation and Up-Regulates Collagen Synthesis and
Min-Ha Choi1, Tae-Sik Jang1, Hyeonwoo Kim1
1From the Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine; Department of Materials Science and Engineering, Chosun University; and R&D Center for Innovative Medicines, Helixmith Co., Ltd.
Background:
Diabetic wounds account for 25 to 50 percent of total diabetic health care costs annually, and present overall healing rates of less than 50 percent. Because delayed diabetic wound healing is associated with impaired fibroblast function, the authors hypothesize that tyrosine kinase Met (cMet) agonistic monoclonal antibody will promote diabetic wound healing by means of stable activation of hepatocyte growth factor/cMet signaling.
Methods:
Two 6-mm dorsal wounds were created in each mouse (6-week-old, male BKS.Cg-Dock7 m +/+Lepr db /J; n = 5). After subcutaneous injections of agonist (20 mg/kg) at 0 and 72 hours, the wound sizes were measured at days 0, 1, 3, 6, and 10. Histologic and immunohistochemical analyses were performed at day 10 (cMet, α-smooth muscle actin, CD68, and transforming growth factor-β). In vitro cytotoxicity and migration tests with diabetic fibroblasts were performed with or without agonist treatment (1 or 10 nM). cMet pathway activation of fibroblasts was confirmed through p-p44/42 mitogen-activated protein kinase, p-mTOR, p-cMet, and ROCK-1 expression.
Results:
The cMet agonistic monoclonal antibody-treated group showed 1.60-fold lower wound area ( p = 0.027), 1.54-fold higher collagen synthesis ( p = 0.001), and 1.79-fold lower inflammatory cell infiltration ( p = 0.032) than the saline-treated control. The agonist increased cMet (1.86-fold; p = 0.029), α-smooth muscle actin (1.20-fold; p = 0.018), and vascular endothelial growth factor (1.68-fold, p = 0.029) expression but suppressed CD68 (1.25-fold; p = 0.043), transforming growth factor-β (1.25-fold; p = 0.022), and matrix metalloproteinase-2 (2.59-fold; p = 0.029) expression. In vitro agonist treatment (10 nM) of diabetic fibroblasts increased their migration by 8.98-fold ( p = 0.029) and activated the hepatocyte growth factor/cMet pathway.
Conclusions:
Tyrosine kinase Met agonistic monoclonal antibody treatment improved diabetic wound healing in mice and reduced wound-site inflammatory cell infiltration. These results need to be validated in large animals before piloting human trials.
Clinical Relevance Statement:
Although further clinical studies are necessary to evaluate its therapeutic efficacy, our study suggested that cMet agonistic monoclonal antibody can be the alternative modality in order to improve wound healing cascade in diabetic foot patients.
Insights
A novel antibody targeting tyrosine kinase Met (cMet) significantly improved diabetic wound healing in mice by enhancing fibroblast function and reducing inflammation. Further studies are needed before human trials for diabetic foot patients.
Area of Science:
- Wound Healing Research
- Diabetic Complications
- Immunotherapy
Background:
- Diabetic wounds have poor healing rates and high healthcare costs.
- Impaired fibroblast function contributes to delayed healing in diabetic wounds.
Purpose of the Study:
- To investigate if a tyrosine kinase Met (cMet) agonistic monoclonal antibody promotes diabetic wound healing.
- To assess the antibody's effect on fibroblast function and hepatocyte growth factor/cMet signaling.
Main Methods:
- Diabetic mice received cMet agonistic antibody injections.
- Wound size, collagen synthesis, and inflammatory cell infiltration were analyzed.
- In vitro tests evaluated diabetic fibroblast migration and pathway activation.
Main Results:
- The antibody-treated group showed significantly reduced wound area and inflammatory cell infiltration.
- Collagen synthesis and fibroblast migration were notably increased.
- Key pathway markers related to healing and inflammation were modulated.
Conclusions:
- cMet agonistic monoclonal antibody treatment effectively improved diabetic wound healing in mice.
- Reduced inflammation and enhanced fibroblast activity were observed.
- Further validation in large animals is recommended prior to human clinical trials.
