ALD1613, A Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology

Abstract

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.

Management challenges and therapeutic advances in congenital adrenal hyperplasia

“…Hypothalamic–pituitary–adrenal axis suppressors Corticotropin-releasing factor receptor 1 (CRF1) antagonist, crinecerfont 126 – 129 : currently ongoing phase III trials CRF1 antagonist, tildacerfont 130 – 133 : currently ongoing phase II trials Adrenocorticotrophic hormone (ACTH) antagonist, ALD1613 (monoclonal antibody) 134 , 135 : about to enter phase I trials ACTH receptor (melanocortin type 2 receptor; MC2R) antagonist, CRN04894 (refs 137 – 139 ): currently ongoing phase I trials …”

“…Adrenocorticotrophic hormone (ACTH) antagonist, ALD1613 (monoclonal antibody) 134 , 135 : about to enter phase I trials…”

Current management of Cushing's disease

“…A study of abiraterone acetate in adrenocortical carcinoma is under way; however, there are currently no published data on the efficacy of abiraterone acetate in CD. Other agents in early stages of development include a monoclonal antibody (ALD1613) that neutralizes ACTH and peptides acting as antagonists of the melanocortin 2 receptor, which aim at inhibiting ACTH action .…”

Pituitary-Directed Therapies for Cushing’s Disease

“…This molecule binds to ACTH with high-affinity and high-specificity thus inhibiting MC2R signaling in vitro . It neutralized ACTH activity in vitro and reduced GC levels in rats and in cynomolgus monkeys ( 112 ). ALD1613 treated rats had also a blunted GC response to stress ( 112 ).…”

“…It neutralized ACTH activity in vitro and reduced GC levels in rats and in cynomolgus monkeys ( 112 ). ALD1613 treated rats had also a blunted GC response to stress ( 112 ). There are no published human studies to date.…”