Hypothalamic–pituitary–adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics.

下丘脑-垂体-肾上腺（HPA）轴功能障碍导致许多人类疾病和失调。我们开发了一种针对肾上腺皮质激素释放因子（CRF）的高亲和力单克隆抗体CTRND05。在小鼠中，CTRND05阻止了应激诱导的皮质酮增加，抵消了慢性可变应激的影响，并诱导了与抑制HPA轴一致的其他表型。CTRND05诱导骨骼肌肥大并增加瘦体重，这是以前没有报道过针对小分子HPA的药物。多器官转录组学通过改变已知的HPA反应性转录本（例如Fkbp5和Myostatin）的水平证明了广泛的HPA轴靶参与，并揭示了诸如Apelin-Apelin受体系统等新颖的HPA反应性途径。