title: 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.
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldhaus
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Katie
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dutzar
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Ethan
authors.initials: E
authors.lastname: Ojala
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Patricia Dianne
authors.initials: PD
authors.lastname: McNeill
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Pei
authors.initials: P
authors.lastname: Fan
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Jenny
authors.initials: J
authors.lastname: Mulligan
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Sam
authors.initials: S
authors.lastname: Marzolf
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Charlie
authors.initials: C
authors.lastname: Karasek
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Michelle
authors.initials: M
authors.lastname: Scalley-Kim
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Erica
authors.initials: E
authors.lastname: Stewart
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Jens
authors.initials: J
authors.lastname: Billgren
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rubin
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schneider
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: David
authors.initials: D
authors.lastname: Jurchen
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Kathy
authors.initials: K
authors.lastname: Snow
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Shaun
authors.initials: S
authors.lastname: Barnett
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bengtsson
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Brian
authors.initials: B
authors.lastname: Baker
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: John A
authors.initials: JA
authors.lastname: Latham
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Dan
authors.initials: D
authors.lastname: Allison
authors.affiliation: Alder BioPharmaceuticals, Inc., Bothell, Washington 98011.
authors.forename: Leon F
authors.initials: LF
authors.lastname: Garcia-Martinez
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D016466:CHO Cells; D003345:Corticosterone / Q000097:blood; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D044103:Receptor, Melanocortin, Type 2 / Q000378:metabolism; D013315:Stress, Psychological / Q000097:blood
chemical_list: C000620778:ALD1613 monoclonal antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D044103:Receptor, Melanocortin, Type 2; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D006854:Hydrocortisone