2区 · 医学
Article
作者: Stewart, Erica ; Rubin, Vanessa ; Feldhaus, Andrew L ; Marzolf, Sam ; McNeill, Patricia Dianne ; Dutzar, Benjamin ; Fan, Pei ; Scalley-Kim, Michelle ; Bengtsson, Barbara ; Mulligan, Jenny ; Anderson, Katie ; Ojala, Ethan ; Schneider, Kathleen ; Karasek, Charlie ; Jurchen, David ; Latham, John A ; Allison, Dan ; Baker, Brian ; Barnett, Shaun ; Garcia-Martinez, Leon F ; Snow, Kathy ; Billgren, Jens
Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.
