CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance

Abstract

MM cells express high levels of CD38, while CD38 is expressed at relatively low levels on normal lymphoid and myeloid cells, and in some non-hematopoietic tissues. This expression profile, together with the role of CD38 in adhesion and as ectoenzyme, resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM). At this moment several CD38 antibodies are at different phases of clinical testing, with daratumumab already approved for various indications both as monotherapy and in combination with standards of care in MM. CD38 antibodies have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Inhibition of ectoenzymatic function and direct apoptosis induction may also contribute to the efficacy of the antibodies to kill MM cells. The CD38 antibodies also improve host-anti-tumor immunity by the elimination of regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Mechanisms of primary and/or acquired resistance include tumor-related factors, such as reduced cell surface expression levels of the target antigen and high levels of complement inhibitors (CD55 and CD59). Differences in frequency or activity of effector cells may also contribute to differences in outcome. Furthermore, the microenvironment protects MM cells to CD38 antibody-induced ADCC by upregulation of anti-apoptotic molecules, such as survivin. Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients.

Keywords: CD38; MOR202; TAK-079; antibody; daratumumab; isatuximab; mode of action; resistance.

Figure 1

Mechanisms of primary and acquired resistance to CD38 antibodies. CD38-targeting antibodies have Fc-dependent immune effector mechanisms: complement-dependent cytoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). NK cells play an important role in CD38 antibody-mediated ADCC, but the possible additional role of other effector cells, such as macrophages, neutrophils, eosinophils, and γδ T-cells, is currently unknown. Daratumumab and isatuximab also have immunomodulatory effects via the eradication of CD38-positive regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells, which is associated with CD4⁺ and CD8⁺ T-cell expansion, and probably a better host-anti-tumor immune response. In addition, CD38 inhibition on T-cells by anti-CD38 antibodies may also contribute to improved anti-tumor activity by increasing NAD+ levels in T-cells. It is currently unknown whether MOR202 has immunomodulatory effects. In addition, isatuximab also directly induces MM cell death by both the classical caspase-dependent apoptotic pathway and lysosomal cell death pathway. Determinants and mechanisms of primary or acquired resistance to these individual modes of action are indicated (in purple), as well as strategies of how to improve these mechanisms of action in order to improve sensitivity and prevent development of resistance (indicated in red). In case the indicated agents have been tested or are being tested in a clinical trial, we added between brackets the CD38 antibody in the combination regimen (D, daratumumab; I, isatuximab; M, MOR202). General mechanisms of resistance include the presence of high-risk cytogenetic abnormailities and development of anti-drug antibodies. Of note, most data with respect to mechanisms of resistance to CD38 antibodies is derived from studies, which evaluated daratumumab. Additional studies are required for isatuximab and MOR202.