Repository corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from the actions of glucocorticoids

Abstract

Repository corticotrophin injection (RCI, H.P Acthar gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half-century, but its mechanism of action is not well understood. We used RNA-Seq methods to define RCI-regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)-4 and CD40 ligand. Following IL-4/CD40L activation and RCI treatment we found up-regulation of 115 unique mRNA transcripts and down-regulation of 80 unique mRNAs. The effect on these RNA levels was dose-dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down-regulated mRNAs were observed to include a significant over-representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids.

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

“…Treatment with Acthar Gel has also been effective in patients with rheumatoid arthritis or glomerular diseases that have been resistant to corticosteroid treatment, further confirming a mechanism of action that is independent of cortisol production [48,49]. Thus, these data, in combination with preclinical and clinical studies [24][25][26]28,48,49], suggest that Acthar Gel may provide benefit in the treatment of inflammatory disease through mechanisms beyond the induction of steroids.…”

“…Taken together, the combined engagement profile of Acthar Gel at MC1R, MC3R, MC4R, and MC5R suggests a distinct direct immune cell effect beyond the indirect antiinflammatory effect from MC2R-dependent production of corticosteroids. Despite less sustained cortisol induction, Acthar Gel remains efficacious [48,49], suggesting direct interaction with immune cells to treat disease [24][25][26]. The mechanism of action of Acthar Gel is unique from that of pACTH 1-39 , ACTH 1-24 , N25D-ACTH 1-39 , and other MCR agonists, suggesting that its complex mixture of peptides interacts with MCRs differently than any single MCR agonist does.…”

“…Acthar V R Gel (repository corticotropin injection; Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA) is a naturally sourced complex mixture of ACTH analogs and other pituitary peptides [23]. Acthar Gel engages the MCRs expressed on immune cells and other tissues throughout the body and is thought to produce both indirect anti-inflammatory and direct immunomodulatory effects [24][25][26]. Acthar Gel is approved for several indications, including treatment of acute exacerbations of multiple sclerosis in adults, as a monotherapy for infantile spasms, and for the induction of diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or due to lupus erythematosus [23].…”

Patient Characteristics and Indicators of Treatment Initiation with Repository Corticotropin Injection in Patients with Rheumatoid Arthritis: A Claims Database Analysis

“…Evaluation of clinical characteristics, treatment patterns, and HCRU before initiation of RCI, versus initiation or continuation of ts/ bDMARD therapy, is critical in understanding differences in patients with uncontrolled RA requiring alternatives to standard therapy and in generating an accurate patient profile for RCI initiators. Repository corticotropin injection is a complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that activates all five melanocortin receptors (MC1R-MC5R), inducing steroidogenesis, antiinflammatory effects, and direct immunomodulation of B and T cells [28][29][30][31][32]. Recently, Montero-Melendez et al demonstrated activation of MC1R-induced cellular senescence in both synovial and dermal fibroblasts in a mouse model of inflammatory arthritis [33].…”

Post Hoc Biomarker Analyses from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Repository Corticotropin Injection (Acthar® Gel) for Persistently Active Systemic Lupus Erythematosus

“…RCI exhibits anti-inflammatory effects that are both steroid-dependent and -independent by binding to all five melanocortin receptors (MCRs) [7,8]. Owing to the wide distribution of MCRs on multiple cell types throughout the body, RCI has the potential to affect several biologic pathways that contribute to inflammation in SLE [9][10][11][12][13][14].…”