A Long-Acting Neutralizing Monoclonal ACTH Antibody Blocks Corticosterone and Adrenal Gene Responses in Neonatal Rats

• Published in: Endocrinology (Philadelphia) Vol. 160; no. 7; pp. 1719 - 1730
• Main Authors: Gehrand, Ashley L, Phillips, Jonathan, Malott, Kevin, Raff, Hershel
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01-07-2019; Oxford University Press
• Subjects: Adrenal glands; Adrenal Glands - drug effects; Adrenal Glands - metabolism; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - blood; Adrenocorticotropic Hormone - immunology; Adrenocorticotropic Hormone - pharmacology; Animals; Animals, Newborn; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - pharmacology; Biological activity; Corticosterone; Corticosterone - blood; Endocrinology; Female; Gene expression; Genetic aspects; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Hypoxia; Hypoxia - metabolism; Juveniles; Long-term effects; Male; Monoclonal antibodies; Neonates; Neutralizing; PD-1 protein; Phosphoproteins - metabolism; Physiological aspects; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Rats; Rats, Sprague-Dawley; Receptors, LDL - metabolism; Stellar age; Steroidogenesis; United States
• DOI: 10.1210/en.2019-00117
• EISSN: 1945-7170
• ISSN: 1945-7170; 0013-7227

Abstract
The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.