CD38 Inhibitor(Ribon Therapeutics)

Acute kidney injury (AKI) encompasses a spectrum of conditions, varying from mild and self-limiting to severe cases that can lead to chronic kidney disease (CKD). Macrophages are crucial in the progression from AKI to CKD, yet the diversity of macrophage subsets complicates the identification of key functional types. We established a detailed single-cell atlas of mononuclear macrophages from the onset of AKI through its progression to CKD. Our results indicate that a macrophage subset with high CD38 expression is closely linked to renal fibrosis following AKI in both mouse model and AKI patients. These CD38^hi macrophages, derived from resident macrophages via Csf1 signaling, secrete the NAD-depleting enzyme CD38, inducing senescence in renal tubular cells and promoting chronic inflammation and renal fibrosis. Knocking out CD38 in macrophages elevated renal NAD levels, reducing senescence and fibrotic responses. Furthermore, we initiated a dosing regimen for a CD38 inhibitor, demonstrating its potential to reduce fibrosis post-AKI, suggesting that targeting CD38^hi macrophages-mediated NAD⁺ metabolism could be a promising therapy to halt AKI to CKD progression.

There are two FDA‐approved anti‐CD38 monoclonal antibodies for treatment of multiple myeloma: isatuximab and daratumumab. Owing to expression of CD38 on reagent red blood cells (RBCs), these antibodies interfere with indirect antiglobulin tests (IATs). We sought to understand differences in such interference by performing binding experiments.

In vitro experiments to compare the binding to RBCs of isatuximab and daratumumab alone or in the presence of a mouse anti‐human CD38 antibody (HB‐7 or AT13/5) or a nicotinamide adenine dinucleotide‐analog CD38 inhibitor were performed and quantified by flow cytometry, imaging, mass spectrometry, surface plasmon resonance, and LigandTracer technologies. Serologic testing was performed on plasma samples spiked with isatuximab or daratumumab.

CD38 expressed on RBCs can be directly bound by daratumumab, whereas isatuximab requires a co‐factor, such as HB‐7, AT13/5, or a CD38 inhibitor, suggesting that the isatuximab epitope on RBCs is masked in vitro. Daratumumab samples more frequently showed interference and had stronger reactions than isatuximab samples. Dithiothreitol treatment was equally effective in mitigating the interference caused by either drug.

Both isatuximab and daratumumab interfere with IATs but at different magnitudes, reflecting distinct binding to CD38 on RBCs. From the binding studies, we conclude that the isatuximab epitope on RBCs is masked in vitro and binding requires a certain CD38 conformation or co‐factor. This circumstance may explain why interference is seen only in a subset of patients receiving isatuximab when compared with interference seen in most patients on daratumumab therapy.