Heavy-chain antibody targeting of CD38 NAD + hydrolase ectoenzyme to prevent fibrosis in multiple organs.

Autor: Shi B; Northwestern Scleroderma Program, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Amin A; Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, 48109, USA., Dalvi P; Teneobio Inc., Menlo Park, CA, 94025, USA., Wang W; Northwestern Scleroderma Program, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Lukacs N; Department of Pathology, The University of Michigan, Ann Arbor, MI, 48109, USA., Kai L; Northwestern Scleroderma Program, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Cheresh P; Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Peclat TR; Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Jacksonville, FL, USA., Chini CC; Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Jacksonville, FL, USA., Chini EN; Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Jacksonville, FL, USA., van Schooten W; Teneobio Inc., Menlo Park, CA, 94025, USA., Varga J; Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, 48109, USA. vargaj@med.umich.edu.; Michigan Scleroderma Program, The University of Michigan, Ann Arbor, MI, 48104, USA. vargaj@med.umich.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Dec 12; Vol. 13 (1), pp. 22085. Date of Electronic Publication: 2023 Dec 12.
DOI: 10.1038/s41598-023-49450-1
Abstrakt: The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD + to ADP-ribose and nicotinamide, CD38 governs organismal NAD + homeostasis and the activity of NAD + -dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD + decline underlying adverse metabolic states, frailty and reduced health span. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by fibrosis in multiple organs. We sought to test the hypothesis that inhibition of the CD38 ecto-enzymatic activity using a heavy-chain monoclonal antibody Ab68 will, via augmenting organismal NAD + , prevent fibrosis in a mouse model of SSc characterized by NAD + depletion. Here we show that treatment of mice with a non-cytotoxic heavy-chain antibody that selectively inhibits CD38 ectoenzyme resulted in NAD + boosting that was associated with significant protection from fibrosis in multiple organs. These findings suggest that targeted inhibition of CD38 ecto-enzymatic activity could be a potential pharmacological approach for SSc fibrosis treatment.
(© 2023. The Author(s).)
Databáze: MEDLINE
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