Y Joyce Huang1, Karen Galen2, Ben Zweifel2, Leah R Brooks3, A Dale Wright2. 1. Cellular and Molecular Biology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. 2. Immunology and Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. 3. Medical Affairs, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA.
Abstract
PURPOSE: To compare the binding and agonistic activity of Acthar® 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 [125I]Nle4, D-Phe7-α-melanocyte-stimulating hormone (α-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 α-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH1-24 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.
PURPOSE: To compare the binding and agonistic activity of Acthar® 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 [125I]Nle4, D-Phe7-α-melanocyte-stimulating hormone (α-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 α-MSH having no activity at MC2R. Acthar Gel treatment had less of an impact on in vivo production of corticosterone compared with synthetic ACTH1-24 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.
Authors: Kyle Hayes; Mary P Panaccio; Parul Houston; John Niewoehner; Mohammed Fahim; George J Wan; Bhavna Dhillon Journal: Open Access Rheumatol Date: 2021-10-15
Authors: Daniel Wynn; Lawrence Goldstick; William Bauer; Enxu Zhao; Eva Tarau; Jeffrey A Cohen; Derrick Robertson; Aaron Miller Journal: CNS Neurosci Ther Date: 2022-01-04 Impact factor: 5.243