An Anti-CRF Antibody Suppresses the HPA Axis and Reverses Stress-Induced Phenotypes
43 Pages Posted: 14 Feb 2019 Sneak Peek Status: Under ReviewMore...
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high affinity, ~1 pM Kd, 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 in lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multi-organ transcriptomics demonstrates broad HPA axis target engagement 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.
Keywords: Corticotropin-releasing factor, glucocorticoids, apelin, antibody, transcriptomics
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