Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family cytokines. It is mainly secreted by T lymphocytes, neutrophils, and macrophages. OSM plays a significant role in inflammation, autoimmunity, and cancers. OSM exerts its pro-inflammatory effect by stimulating the production of chemokines by endothelial cells and inducing neutrophil chemotaxis and adhesion. The high levels of OSM protein and mRNA usually occur in patients with rheumatoid arthritis, asthma, pulmonary fibrosis, and atopic dermatitis.
IL-31 is an inflammatory cytokine. It is secreted by activated CD4+ T lymphocytes. Its main function is to facilitate cell-mediated immunity against pathogens. Besides, IL-31 signals through a receptor complex which consists of IL-31 receptor A (IL31RA) and OSM receptor (OSMR) subunits. Although OSMR does not bind to IL-31 in normal cases, it does increase the IL-31 binding affinity to IL-31RA. Elevated IL-31 occurs in patients with atopic dermatitis and prurigo nodularis. Therefore, the inhibition of OSM and IL-31 is a strategy for treating inflammation.
Vixarelimab (KPL-716) is a human anti-OSM monoclonal antibody and inhibits IL-31.
It can bind to the beta chain of the OSM receptor as well as inhibit IL-31 and OSM signaling on oncostatin M-stimulated keratinocytes and fibroblast.
Following the experiments in vitro, Vixarelimab (0.0001-0.1 μg/mL) resulted in increased MCP-1/CCL2 levels at a concentration of 0.0001 μg/mL in human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) cells. Also, it significantly decreased MCP-1/CCL2 levels in both cells at concentrations of 0.001 μg/mL or higher. Moreover, this antibody (0.0001-0.1 μg/mL) pretreatment results in reduced levels of MCP-1/CCL2 in both OSM induced as well as OSM plus IL-4-induced HEK and HDF cells and the maximum effect shows at concentrations of 0.01 μg/mL and 0.1 μg/mL.
Furthermore, in a cynomolgus monkey model, KPL-716 attenuated the scratching response to supra-physiologic doses of IL-31. Importantly, in the clinical setting, a single dose of KPL-716 improved pruritus in patients with atopic dermatitis.
In conclusion, Vixarelimab is a potent monoclonal antibody that inhibits OSM signaling and IL-31. It has the potential to treat inflammatory skin diseases such as atopic dermatitis and itchy nodular rash.
1. Carl D Richards, et al. Acta Derm Venereol. 2020 Jul 2;100(14):adv00197.
2. Zamaneh Mikhak, et al. First-in-Human Study of KPL-716, Anti-Oncostatin M Receptor Beta Monoclonal Antibody, in Healthy Volunteers and Subjects With Atopic Dermatitis