Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

Ghose, Jayeeta; Viola, Domenico; Terrazas, César; Caserta, Enrico; Troadec, Estelle; Khalife, Jihane; Gunes, Emine Gulsen; Sanchez, James F.; McDonald, Tinisha; Marcucci, Guido; Kaur, Balveen; Rosenzweig, Michael; Rosen, Steven T.; Krishnan, Amrita; Satoskar, Abhay R.; Hofmeister, Craig C.; Pichiorri, Flavia

doi:10.1080/2162402x.2018.1486948

Cited by 48 publications

(36 citation statements)

References 66 publications

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“…Resistance to ADCC (e.g., fratricidal depletion of CD38+ NK cells), CDC (e.g., upregulation of complement-inhibitory molecules) and ADCP (e.g., upregulation of CD47 inhibiting phagocytosis) have been observed during anti-CD38 mAb treatment and strategies to overcome them are under clinical investigation [96]. Nevertheless, the most relevant issue limiting retreatment with anti-CD38 mAbs is the long-lasting downregulation of CD38 on plasma cell surfaces after anti-CD38 therapy [97]. Even though strategies to reinduce CD38 expression in malignant plasma cells are under clinical investigation [98,99], changing the target antigen may be a more appealing strategy in RRMM patients who are refractory to anti-CD38 treatment.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

D’Agostino

Innorcia

Boccadoro

et al. 2020

IJMS

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Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs.

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Section: Future Directions and Conclusionmentioning

confidence: 99%

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

D’Agostino

Innorcia

Boccadoro

et al. 2020

IJMS

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“…Lower basal levels of the target antigen have been proposed as a possible mechanism of intrinsic resistance to mAbs [122,123]. Regarding daratumumab, the downregulation of CD38 on cell surfaces could partially explain the loss of response to mAb therapy [124]. Interestingly, myeloma cells exposed to isatuximab and MOR202 did not show such a downregulation [125,126].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bonello

Mina

Boccadoro

2019

Cancers

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Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs ® ), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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“…These results indicate that dynasore somehow inhibited CCND1 and CDK4 expression so that CCND1-CDK4 complexes decreased, which leads to hypophosphorylation of pRb and block G1-S transition. Since identified, dynasore was widely used in the researches of endocytosis and macropinocytosis as a dynamin inhibitor 11,12,31–33 . In the latest reports, dynasore was found to be able to repress cell proliferation, migration of lung cancer cell lines in vitro 18,19 , and, consist with our results, dynasore augmented the anti-cancer effects of cisplatin 18 .…”

Section: Discussionmentioning

confidence: 99%

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

Zhong

Shi

et al. 2019

Cell Death Dis

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Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients' health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

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Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

Cited by 48 publications

References 66 publications

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

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