Examine the Roles of Complement C5a Receptors in Hidradenitis Suppurativa by ex Vivo Studies

Hidradenitis suppurativa is a debilitating chronic inflammatory follicular skin disease. The estimated prevalence of HS range between 1 and 4%, even though it has been an underdiagnosed disease until recently (Revuz J, 2009). In the acute stage, patients present with painful inflamed nodules (boils) and abscesses in the groin, buttocks and axillae. In a late stage sinus tract formation and scarring occurs. Treatment options include the antibiotics, anti-TNF and surgical methods (wide excisions and deroofing). However, most patients do not respond, or only respond partially or temporarily to treatments (von der Werth JM, 2001; Napolitano M, 2017; Nazary M, 2011; van der Zee HH, 2012).

The pathogenesis of HS is largely unknown, and possible causes include plugged apocrine gland or hair follicle, excessive sweating, androgen dysfunction and genetic disorders. Defective cytokine responses and the infiltration of a variety of immune cells suggest the autoinflammatory nature of the disease (Giamarellos-Bourboulis EJ, 2007; van der Zee HH; 2011; van der Zee HH, 2012), which is in line with the significant improvement seen in patients administered the tumor necrosis factor-a (TNF-a) blocker adalimumab (Kimball AB, 2016). Neutrophils have been identified in skin lesions and are considered to be the major cell type to produce pus. Complement C5a is a major chemotactic factor that stimulates neutrophil infiltration. The role of C5a has just recently started to be studied in HS. (Blok JL, 2016; Kanni T, 2018). An open label phase 2 study demonstrated that a 50% HS clinical response rate was achieved in up to 83% of patients receiving an C5a antibody (IFX-1, NCT 03001622). Thus, targeting the C5a signaling may represent a promising therapeutic strategy in HS.

Most of the C5a effects result from binding to the canonical complement 5a receptor 1, C5aR. However, there is a second C5a receptor, C5L2, whose roles are still controversial. Both pro- and anti-inflammatory properties have been proposed for C5L2. These contradictory results may be dependent on specific physiological or pathological conditions (Zhang T, 2017). ChemoCentryx has a series of potent and selective small molecule C5aR inhibitors (C5aRi) that are being developed for inflammatory diseases such as ANCA associated vasculitis, C3 glomerulopathy and HS. In this proposal, we will use these C5aRi to examine the differential effects of targeting C5aR.

Study Design

An ex vivo skin culture system will be utilized to examine the effects of C5aR inhibition on neutrophil activation/inflammatory activities. Four-millimeter (4mm) lesional and perilesional skin biopsies will be taken from skin excisions of 40 patients with known Hidradenitis Suppurativa. Surplus skin excision material from "deroofment" treatment of HS patients will be used. Peri-lesional and lesional biopsies will be collected for comparison. These samples will be delivered to ChemoCentryx for direct analysis or treatment with C5a and/or C5a inhibitors. Analysis will include but not limited to histological analysis, examining immune cell populations and surface markers, protein and gene expression levels of complement factors, cytokines and chemokines. Flow cytometry, immunohistochemistry, ELISA and other standard assays will be used for these analyses. These studies will extend the on-going studies with Dr. Kavita and colleagues, and will test the hypothesis that continued activation of neutrophils and other C5a-expressing leukocytes in the skin lesions of HS patients contribute to tissue damage.