Abstract
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.
Highlights
Epidemiological and biomarker studies have associated both bind with high-affinity to CRFR1, whereas all UCNs bind CRFR2 early-life or long-term psychological stress as well as alterations with high affinity
Recombinant adeno-associated virus–mediated overexpression of corticotropin-releasing factor (CRF) (Fig. S1 K; Chakrabarty et al, 2013) leads to a cushingoid phenotype in mice, similar to that seen in CRF-overexpressing transgenic mice (Wang et al, 2011), and a single 25 mg/kg i.p. injection of CTRND05 reversed the hair loss seen in these mice
We evaluated the ability of UCNs to compete with CRF for CTRND05 binding via direct competitive ELISA
Summary
Epidemiological and biomarker studies have associated both bind with high-affinity to CRFR1, whereas all UCNs bind CRFR2 early-life or long-term psychological stress as well as alterations with high affinity. We report on the development of a mouse monoclonal antibody, CTRND05, that binds CRF with high affinity (∼1 pM Kd) and dose-dependently suppresses HPA axis activation in mice following peripheral administration.
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