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An Anti-CRF Antibody Suppresses the HPA Axis and Reverses Stress-Induced Phenotypes

43 Pages Posted: 14 Feb 2019 Sneak Peek Status: Under Review

See all articles by Hunter S. Futch

Hunter S. Futch

University of Florida - McKnight Brain Institute; University of Florida - Center for Translational Research in Neurodegenerative Disease

Karen N. McFarland

University of Florida - Center for Translational Research in Neurodegenerative Disease; University of Florida - McKnight Brain Institute

Brenda D. Moore

University of Florida - McKnight Brain Institute; University of Florida - Center for Translational Research in Neurodegenerative Disease

M. Zino Kuhn

University of Florida - Center for Translational Research in Neurodegenerative Disease; University of Florida - McKnight Brain Institute

Benoit I. Giasson

University of Florida - McKnight Brain Institute; University of Florida - Center for Translational Research in Neurodegenerative Disease

Thomas B. Ladd

University of Florida - McKnight Brain Institute; University of Florida - Center for Translational Research in Neurodegenerative Disease

Karen A. Scott

University of Florida - McKnight Brain Institute; University of Florida - Department of Pharmacodynamics

Melanie R. Shapiro

University of Florida - Diabetes Institute

Rachel L. Nosacka

University of Florida - Department of Physical Therapy

Marshall S. Goodwin

University of Florida - McKnight Brain Institute

Yong Ran

University of Florida - McKnight Brain Institute

Pedro E. Cruz

University of Florida - McKnight Brain Institute

Daniel H. Ryu

University of Florida - McKnight Brain Institute

Cara L. Croft

University of Florida - McKnight Brain Institute

Yona Levites

University of Florida - McKnight Brain Institute

Christopher Janus

University of Florida - McKnight Brain Institute

Paramita Chakrabarty

University of Florida - McKnight Brain Institute

Andrew R. Judge

University of Florida - Department of Physical Therapy

Todd M. Brusko

University of Florida - Diabetes Institute

Annette D. de Kloet

University of Florida - McKnight Brain Institute

Eric G. Krause

University of Florida - McKnight Brain Institute

Todd Golde

University of Florida - Center for Translational Research in Neurodegenerative Disease; University of Florida - McKnight Brain Institute

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Abstract

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

Suggested Citation

Futch, Hunter S. and McFarland, Karen N. and Moore, Brenda D. and Kuhn, M. Zino and Giasson, Benoit I. and Ladd, Thomas B. and Scott, Karen A. and Shapiro, Melanie R. and Nosacka, Rachel L. and Goodwin, Marshall S. and Ran, Yong and Cruz, Pedro E. and Ryu, Daniel H. and Croft, Cara L. and Levites, Yona and Janus, Christopher and Chakrabarty, Paramita and Judge, Andrew R. and Brusko, Todd M. and de Kloet, Annette D. and Krause, Eric G. and Golde, Todd, An Anti-CRF Antibody Suppresses the HPA Axis and Reverses Stress-Induced Phenotypes (February 14, 2019). Available at SSRN: https://ssrn.com/abstract=3334424 or http://dx.doi.org/10.2139/ssrn.3334424
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hunter S. Futch

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

Karen N. McFarland

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

Brenda D. Moore

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

M. Zino Kuhn

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

Benoit I. Giasson

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

Thomas B. Ladd

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

University of Florida - Center for Translational Research in Neurodegenerative Disease

Gainesville, FL 32610
United States

Karen A. Scott

University of Florida - McKnight Brain Institute

Gainesville, FL 32610
United States

University of Florida - Department of Pharmacodynamics

Gainesville, FL 32610
United States

Melanie R. Shapiro

University of Florida - Diabetes Institute

Gainesville, FL 321610
United States

Rachel L. Nosacka

University of Florida - Department of Physical Therapy

Gainesville, FL 32610
United States

Marshall S. Goodwin

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Yong Ran

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Pedro E. Cruz

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Daniel H. Ryu

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Cara L. Croft

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Yona Levites

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Christopher Janus

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Paramita Chakrabarty

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Andrew R. Judge

University of Florida - Department of Physical Therapy

Gainesville, FL 32610
United States

Todd M. Brusko

University of Florida - Diabetes Institute

Gainesville, FL 321610
United States

Annette D. De Kloet

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Eric G. Krause

University of Florida - McKnight Brain Institute

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Todd Golde (Contact Author)

University of Florida - Center for Translational Research in Neurodegenerative Disease ( email )

Gainesville, FL 32610
United States

University of Florida - McKnight Brain Institute ( email )

Gainesville, FL 32610
United States

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