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

Abstract

Purpose: To compare the binding and agonistic activity of Acthar V R Gel and synthetic melanocortin receptor (MCR) agonists and examine how the activity of select agonists affects the in vivo production of corticosterone. Materials and Methods: In vitro binding was determined using concentration-dependent displacement of the ligand [ 125 I]Nle 4 , D-Phe 7-a-melanocyte-stimulating hormone (a-MSH) on cells expressing MC1R, MC3R, MC4R, or MC5R. Functional activity was determined using a time-resolved fluorescence cyclic adenosine monophosphate (cAMP) assay in cells expressing MC1R, MC2R, MC3R, MC4R, or MC5R. In vivo corticosterone analyses were performed by measuring plasma corticosterone levels in Sprague Dawley rats. Results: Acthar Gel and synthetic MCR agonists exhibited the highest binding at MC1R, lowest binding at MC5R, and moderate binding at MC3R and MC4R. Acthar Gel stimulated the production of cAMP in all 5 MCR-expressing cell lines, with MC2R displaying the lowest level of full agonist activity, 3-, 6.6-, and 10-fold lower than MC1R, MC3R, and MC4R, respectively. Acthar Gel was a partial agonist at MC5R. The synthetic MCR agonists induced full activity at all 5 MCRs, with the exception of a-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH 1-24 depot. Conclusions: Acthar Gel bound to and activated each MCR tested in this study, with partial agonist activity at MC5R and the lowest level of full agonist activity at MC2R, which distinguished it from synthetic MCR agonists. The minimal activity of Acthar Gel at MC2R corresponded to lower endogenous corticosteroid production.

A Prospective Observational Registry of Repository Corticotropin Injection (Acthar® Gel) for the Treatment of Multiple Sclerosis Relapse

“…The therapeutic benefits of RCI are often ascribed to endogenous corticosteroid production resulting from the activation of melanocortin receptor 2 (MC2R). However, recent evidence from preclinical studies suggests that RCI activates MC2R to a lesser extent than other ACTH formulations and, consequently, stimulates less endogenous corticosteroid production (8,9). Additionally, the immunomodulatory and anti-inflammatory effects of RCI may be mediated through corticosteroid-independent mechanisms via engagement of MC1R, MC3R, MC4R, and MC5R on immune cells (8,(10)(11)(12)(13).…”

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

“…The complex mixture of adrenocorticotropic hormones and pituitary peptides in RCI functionally activates the MCRs in preferential order, with the greatest activity observed on MC4R, MC3R, and MC1R signaling, followed by MC2R and a partial agonist effect on MC5R. This is distinct from synthetic adrenocorticotropic hormone (ACTH) 1–24, which shows greatest activity on MC2R, resulting in higher endogenous glucocorticoid production by ACTH 1-24 compared with RCI [ 34 ]. This difference in MCR engagement and activation may explain the potential for RCI action through non-steroidogenic mechanisms.…”

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

“…Repository corticotropin injection (RCI; Acthar Ò Gel) is US Food and Drug Administration approved for use during an exacerbation or as maintenance therapy in select cases of SLE [7]. RCI is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is thought to exhibit steroid-dependent and steroid-independent anti-inflammatory effects by engaging all five melanocortin receptors [8][9][10][11][12]. RCI is effective in the treatment of persistently active SLE that is not responsive to standard-of-care therapies [13][14][15][16][17].…”