The Circular Life of Human CD38: From Basic Science to Clinics and Back

Abstract

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

CD38 in the age of COVID-19: a medical perspective

“…NAD 1 -glycohydrolase, the main enzymatic activity of CD38, is not modified in the presence of anti-CD38 human or murine antibodies. On the contrary, cyclase activity is highly inhibited, while hydrolase activity is mildly activated (41)(42)(43). These data provide further support for considering extracellular CD38 primarily as a NAD 1 -glycohydrolase (44).…”

PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

“…Consistently, PD-1 expression seems to be increased in MM patients as compared to HD or MGUS patients. Together with PD-1/PD-L1, many studies indicate that CD38 is involved in the immunosuppression induced by MM cells through the production of ADO [ 102 ]. Interestingly, recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, CD38 metabolic pathways could play an important role.…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…CD38/NAD+-glycohydrolase is expressed in many cell types as a multifunctional enzyme mainly acting on NAD+ to convert it to cyclic ADP-ribose with Ca2+-mobilizing activity [ 74 , 75 , 76 ]. Due to its oligomeric structure, CD38 behaves as a catalytically active transporter responsible for the generation and entry of cyclic ADP-ribose into the cell, whereas astroglial connexin 43 (Cx43) might be functionally coupled with CD38 to provide NAD+ access to the active site of CD38 [ 75 ].…”