Daratumumab: Beyond Multiple Myeloma

Ejaz, Kiran; Roback, John D.; Stowell, Sean R.; Sullivan, Harold C.

doi:10.1016/j.tmrv.2021.06.002

Cited by 10 publications

(8 citation statements)

References 63 publications

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“…The observation that the naïve T cell compartment exhibited higher CD38 expression compared to its effector counterparts might have significant clinical implications since CD38 monoclonal antibody is used to treat patients with multiple myeloma via antibody-dependent cellular cytotoxicity and is currently being investigated in clinical trials for chronic lymphocytic leukemia ( 8 , 10 ). Recently, Krejcik et al.…”

Section: Discussionmentioning

confidence: 99%

“…A plethora of studies found higher expression of CD38 in various pathological conditions including cancers, autoimmune diseases and chronic viral infections, and identified its involvement in various biological processes including cell differentiation, cell migration, cytokine secretion, and apoptosis ( 2 – 6 ), suggesting it to be an important therapeutic target for treating cancers and autoimmune diseases ( 7 ). Monoclonal antibodies such as Daratumumab and Isatuximab have indeed shown encouraging results for the treatment of lymphoid cancers and autoimmune diseases ( 8 – 11 ). However, monoclonal antibody treatment, such as Daratumumab, results in clearance of CD38+ pathological cells by antibody dependent cellular cytotoxicity (ADCC), but it also increases risk of infections due to the depletion of CD38+ non-pathological immune cells ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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CD38: an ecto-enzyme with functional diversity in T cells

et al. 2023

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CD38, a nicotinamide adenine dinucleotide (NAD)+ glycohydrolase, is considered an activation marker of T lymphocytes in humans that is highly expressed during certain chronic viral infections. T cells constitute a heterogeneous population; however, the expression and function of CD38 has been poorly defined in distinct T cell compartments. We investigated the expression and function of CD38 in naïve and effector T cell subsets in the peripheral blood mononuclear cells (PBMCs) from healthy donors and people with HIV (PWH) using flow cytometry. Further, we examined the impact of CD38 expression on intracellular NAD+ levels, mitochondrial function, and intracellular cytokine production in response to virus-specific peptide stimulation (HIV Group specific antigen; Gag). Naïve T cells from healthy donors showed remarkably higher levels of CD38 expression than those of effector cells with concomitant reduced intracellular NAD+ levels, decreased mitochondrial membrane potential and lower metabolic activity. Blockade of CD38 by a small molecule inhibitor, 78c, increased metabolic function, mitochondrial mass and mitochondrial membrane potential in the naïve T lymphocytes. PWH exhibited similar frequencies of CD38+ cells in the T cell subsets. However, CD38 expression increased on Gag-specific IFN-γ and TNF-α producing cell compartments among effector T cells. 78c treatment resulted in reduced cytokine production, indicating its distinct expression and functional profile in different T cell subsets. In summary, in naïve cells high CD38 expression reflects lower metabolic activity, while in effector cells it preferentially contributes to immunopathogenesis by increasing inflammatory cytokine production. Thus, CD38 may be considered as a therapeutic target in chronic viral infections to reduce ongoing immune activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD38: an ecto-enzyme with functional diversity in T cells

et al. 2023

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“…Daratumumab (DARA) and other monoclonal anti‐CD38 antibodies represent vital treatments for multiple myeloma, and their medical applications continue to expand. Unfortunately, monoclonal anti‐CD38 antibodies bind to CD38 expressed on red blood cells (RBCs), causing panreactivity in indirect antiglobulin tests (IATs) 1–5 . Plasma samples from patients receiving anti‐CD38 consistently cause positive agglutination reactions in antibody detection tests (screens), antibody identification panels, and antihuman globulin cross matches, complicating pretransfusion testing and potentially delaying patient blood support.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, monoclonal anti-CD38 antibodies bind to CD38 expressed on red blood cells (RBCs), causing panreactivity in indirect antiglobulin tests (IATs). [1][2][3][4][5] Plasma samples from patients receiving anti-CD38 consistently cause positive agglutination reactions in antibody detection tests (screens), antibody identification panels, and antihuman globulin cross matches, complicating pretransfusion testing and potentially delaying patient blood support. Several strategies have been employed to negate the anti-CD38 interference, each with advantages and disadvantages.…”

Section: Introductionmentioning

confidence: 99%

Efficient neutralization of daratumumab in pretransfusion samples using a novel recombinant monoclonal anti‐idiotype antibody

Aung

Spencer²,

Potter

et al. 2022

Transfusion

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Background Anti‐CD38 antibodies such as daratumumab (DARA) are critical therapies for multiple myeloma and other diseases. Unfortunately, anti‐CD38 antibodies cause panreactivity in indirect antiglobulin tests (IATs), complicating blood compatibility testing. The anti‐CD38 interference is most often mitigated by treating reagent red blood cells (RBCs) with dithiothreitol (DTT). However, when using the DTT method, not all RBC antibody specificities can be detected (e.g., anti‐K), and the DTT method is impractical for some transfusion services. We evaluated the ability of a new anti‐idiotype antibody to neutralize DARA in vitro and eliminate the anti‐CD38 interference. Study Design and Methods A recombinant monoclonal rabbit anti‐DARA idiotype antibody (“anti‐DARA”) was generated. The ratio of anti‐DARA required to neutralize DARA in spiked samples was evaluated in IATs performed in gel. IATs performed in tube were used to demonstrate that anti‐DARA allows alloantibody detection in the presence of DARA. Plasma samples from 29 patients receiving DARA were treated with a fixed quantity of anti‐DARA (120 μg) before performing antibody detection tests (screens) in tube. Results Anti‐DARA used at or above a 1:1 ratio with DARA eliminated the DARA interference with IATs. Anti‐DARA allowed detection of both alloanti‐E and alloanti‐K in the presence of DARA. In 27/29 (93.1%) clinical samples, 120 μg anti‐DARA was sufficient to neutralize the DARA in 100 μl patient plasma. Discussion An anti‐DARA:DARA ratio as low as 1:1 is sufficient to neutralize DARA in solution. A fixed amount of anti‐DARA eliminates the anti‐CD38 interference in most patient samples.

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“…Do these alloantibody results generalize to patient groups other than those with multiple myeloma, including children? Data suggest that daratumumab could be effective in managing autoimmune hemolytic anemia, antibody‐mediated rejection in solid organ transplantation, and various other diseases with autoimmune etiologies 16 . Further studies are needed to observe the incidence of RBC alloimmunization in patients treated with daratumumab for these diseases before results from patients with multiple myeloma can be extrapolated.…”

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confidence: 99%