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

Sci Rep. 2023 Dec 12;13(1):22085. doi: 10.1038/s41598-023-49450-1.

Abstract

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.

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1 / metabolism
  • Animals
  • Antigens, CD* / metabolism
  • Antigens, Differentiation* / metabolism
  • Fibrosis
  • Glycoside Hydrolases
  • Membrane Glycoproteins / metabolism
  • Mice
  • NAD / metabolism
  • NAD+ Nucleosidase / metabolism

Substances

  • ADP-ribosyl Cyclase 1
  • Antigens, CD
  • Antigens, Differentiation
  • NAD+ Nucleosidase
  • NAD
  • ADP-ribosyl Cyclase
  • Membrane Glycoproteins
  • Glycoside Hydrolases