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

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.