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

Roccatello, Dario; Fenoglio, Roberta; Sciascia, Savino; Naretto, Carla; Rossi, Daniela; Ferro, Michela; Barreca, Antonella; Malavasi, Fabio; Baldovino, Simone

doi:10.3390/ijms21114129

Cited by 23 publications

(18 citation statements)

References 66 publications

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“…A multicentric retrospective study showed the feasibility and effectiveness of DARA in relapsed/refractory AL (Amyloid light chain) amyloidosis suggesting its use early in the course of disease [ 77 ]. Other supporting data can be found in the literature [ 78 , 79 , 80 ].…”

Section: Clinical Applications Outside MMsupporting

confidence: 74%

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

et al. 2020

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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.

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Section: Clinical Applications Outside MMsupporting

confidence: 74%

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

et al. 2020

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“…Our data correlated with those from a previous case report [ 13 ] and with the currently reported results of phase I/II trials for patients with MM [ 14 , 15 ]. A case report of a patient with relapsed plasma cell leukemia and t(11;14) treated with a combination therapy of venetoclax, daratumumab, and dexamethasone showed a rapid decrease in tumor burden [ 13 ].…”

Section: Discussionsupporting

confidence: 91%

“…Among these patients, 46% were refractory to PI, 71% were refractory to IMiDs, and 42% were double refractory to PI and IMiDs. The ORR of patients with t(11;14) treated by VenDd therapy was 92%, while that for patients treated with venetoclax (Ven) in combination with daratumumab (D), dexamethasone (d), and bortezomib (V) (VenDVd) therapy was 88%; this demonstrated a significant efficacy of the combination treatment [ 14 , 15 ]. Our data are also useful for establishing the optimal dose for each of the drugs.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma

Nakamura

Suzuki

Kanasugi

et al. 2021

IJMS

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The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.

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“…CD38 is a transmembrane glycoprotein molecule that plays an important role in cell adhesion and is heavily present in clonal PCs [ 98 ]. Daratumumab is a humanized monoclonal antibody against CD38 that can initiate antibody-mediated cellular toxicity along with complement-mediated cytotoxicity [ 99 ].…”

Section: Monoclonal Antibodies Targeting Cd38mentioning

confidence: 99%

Current Updates on the Management of AL Amyloidosis

El‐Sayed¹,

Usher²,

Habib³

et al. 2021

J Hematol

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Systemic immunoglobulin light chain (AL) amyloidosis is a rare but fatal disease. It results from clonal proliferation of plasma cells with excessive production of insoluble misfolded proteins that aggregate in the extracellular matrix, causing damage to the normal architecture and function of various organs. For decades, treatment for AL amyloidosis was based mainly on therapeutic agents previously studied for its more common counterpart, multiple myeloma. As the prevalence and incidence of AL amyloidosis have increased, ongoing research has been conducted with treatments typically used in myeloma with varying success. In this review, we focus on current treatment strategies and updates to clinical guidelines and therapeutics for AL amyloidosis.

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

Cited by 23 publications

References 66 publications

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

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

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma

Current Updates on the Management of AL Amyloidosis

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