Mechanism of Action of a New Anti-CD38 Antibody: Enhancing Myeloma Immunotherapy

Abstract

Antibody therapy is a treatment option for several diseases, including multiple myeloma. The logic behind it is relatively simple: A target molecule is selected because of its expression on tumor cells, and the antibody delivers cytotoxic effects.Therapeutic results in multiple myeloma indicate that the anti-CD38 antibodies may have relevant immunotherapeutic properties.See related article by Moreno et al., p. 3176 In this issue of Clinical Cancer Research, Moreno and colleagues (1) provide an original analysis of the characteristics of a new chimeric anti-CD38 antibody candidate for multiple myeloma therapy.The initial promise of mAb, heralded as a "magic bullet" for cancer therapy, was not immediately fulfilled. Decades of frustrating results were necessary before the clinical success of anti-CD20 antibodies finally rewarded the efforts of clinicians and pharmaceutical companies, rekindling interest in pursuing the development of antibody-based therapies. This required rethinking the role of antibodies in vivo: it is now accepted that some antibodies block the function of a membrane receptor while others synergize it. Synergistic antibodies occupy a domain that hosts the site of the natural ligand of the molecule (molecular mimicry). When the target lies in close proximity to professional receptors, it can trigger signals (molecular parasitism). CD38, functionally associated with the B-cell receptor (BCR), the T-cell receptor (TCR), and CD16A (the low-affinity IgG FcR; ref.2), is one example.These conclusions are relatively straightforward when the function of the target molecule is known. However, such is not the case for CD38, whose precise roles are not yet fully known. The results of antibody therapy following the introduction of daratumumab (3) have provided useful practical and theoretical information about the functions of the target and, at the same time, revealed some unexpected mechanisms of action (MoA) of therapeutic antibodies in vivo. The findings presented by Moreno and colleagues indicate that isatuximab has unique characteristics, only some of which are shared with daratumumab. In fact, given their different MoAs, the two antibodies might be potentially valuable as therapeutic complements or alternatives in patients developing resistance to one of them. The particular benefit provided by isatuximab is its sensitivity to the number of CD38 molecules present on target cells. Isatuximab saturates membrane CD38 and can be internalized. However, antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) are triggered only when the number of surface CD38 molecules reaches a threshold. The same thing happens in the induction of direct apoptosis. Isatuximab does not alter the transcription on a high CD38 þ myeloma line.The existence of such a threshold was established by quantifying the number of CD38 molecules expressed both by multiple myeloma and by the majority of normal cell populations. Isatuximab may have a lower deple...

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

“…DARA, a human mAb, reacts with the CD38 molecule in epitopes distant from its catalytic site. ISA, a humanized mAb, displays peculiar characteristics recently described [ 38 , 39 ]. The effects of ISA are reported as being extremely sensitive to the number of CD38 molecules present per cell surface.…”

CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond

“…As NK cells mediate ADCC, these cells have a main role in enhancing the activity of anti-CD38 MoAbs [53][54][55][56][57]. DARA increases NK-cell cytotoxicity against cells expressing high, but not low, CD38 [50].…”

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

“…Given the important expression of Fc receptors (FcR) on DC, 23 we cannot exclude that the anti-CD38 monoclonal antibody may react simultaneously on the same cell via their binding site and also via FcR by implementing the so-called scorpion effect. 24 Nevertheless, ultimately, we observed a depletion of the DC in our patients upon Dara treatment. Overall, this suggests that targeting CD38 in MM may contribute to restore antitumor immune response mediated by DC and cytotoxic T cells, through a continuous depletion of these cell subsets, preventing PD-L1 upregulation.…”

“…In contrast, in the Dara group, as DC subsets are continuously depleted by Dara, we hypothesized that the low PD‐L1 expression was the reflect of the expression level on de novo produced DC. Given the important expression of Fc receptors (FcR) on DC, we cannot exclude that the anti‐CD38 monoclonal antibody may react simultaneously on the same cell via their binding site and also via FcR by implementing the so‐called scorpion effect . Nevertheless, ultimately, we observed a depletion of the DC in our patients upon Dara treatment.…”