Inhibition of CD38 enzyme activity on engrafted human immune cells enhances NAD+ metabolism and inhibits inflammation in anmodel of xeno-GvHD.

Abstract

INTRODUCTION: CD38 is highly expressed on immune cells. It catabolizes NAD+, which is a critical cofactor for enzymes involved in metabolism and energy production. METHODS AND RESULTS: We developed TNB-738, a fully human antibody that potently inhibits human CD38 enzymatic activity on human immune cells, resulting in a dose-dependent increase of intracellular NAD+ levels. TNB-738 does not show immune effector functions, does not induce direct cell killing of CD38 positive cells and is not internalized. In vivo, treatment with TNB-738 following infusion of human PBMCs into NSG mice resulted in significantly lower clinical scores, prolonged overall survival, less expansion of engrafted human CD45+ cells and a significant expansion of Tregs. DISCUSSION: CD38 positive T cells regulate NAD+ metabolism in inflamed tissues and blockade of CD38 enzyme activity by TNB-738 could represent a novel class of therapeutics for the treatment of inflammatory conditions, including GvHD.