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J Exp Med. 2019 Aug 29. pii: jem.20190430. doi: 10.1084/jem.20190430. [Epub ahead of print]

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

Author information

1
McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience and Neurology, College of Medicine, University of Florida, Gainesville, FL.
2
McKnight Brain Institute, Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL.
3
Diabetes Institute, Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
4
Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, FL.
5
McKnight Brain Institute, Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL.
6
McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience and Neurology, College of Medicine, University of Florida, Gainesville, FL tgolde@ufl.edu.

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.

PMID:
31467037
DOI:
10.1084/jem.20190430

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