Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection

Oberle, Anna; Brandt, Anna; Alawi, Malik; Langebrake, Claudia; Janjetovic, Snjezana; Wolschke, Christine; Schütze, Kerstin; Bannas, Peter; Kröger, Nicolaus; Koch-Nolte, Friedrich; Bokemeyer, Carsten; Binder, Mascha

doi:10.3324/haematol.2017.169235

Cited by 53 publications

(34 citation statements)

References 14 publications

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“…Such approaches will also have to take into account the potential interference of diagnostic antibodies directed at the same epitope as therapeutic antibodies (daratumumab, elotuzumab), e.g. by utilizing antibodies prone to different epitopes on the same target molecule [30]. Mass cytometry has recently been developed as a variation of flow cytometry that detects heavy metal-ion tagged antibodies using time-offlight mass spectrometry.…”

Section: Identification and Enumeration Of Cmmcs By Flow Cytometrymentioning

confidence: 99%

Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease

Waldschmidt

Anand

Knoechel

et al. 2018

Seminars in Hematology

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The presence or absence of minimal residual disease (MRD) in patients with multiple myeloma (MM) has emerged as a useful marker to determine the depth of remission. MRD negativity as an endpoint has been shown to be associated with improved progression-free survival in many studies. MRD detection is therefore part of numerous clinical trial protocols for MM. At the present time, two methodologies are most widely accepted for MRD detection: (1) multicolor flow cytometry and (2) next-generation sequencing-based clonotype detection. While both of those methodologies enable accurate quantification of MRD in the bone marrow (BM), with sensitivity as low as 10 to 10, there are several limitations to these methods. First, these approaches reveal the presence or absence of MRD but provide limited molecular information about MM. More comprehensive characterization of MM cells at the MRD stage may identify molecular mechanisms of drug resistance. Second, MRD detection in the BM is typically performed at one time point only, but more frequent detection may define the duration of the MRD status and thus refine its prognostic value. Third, less-invasive approaches that avoid the discomfort and risk associated with BM biopsy would be highly desirable, especially in elderly or frail patients. "Liquid biopsy" for the detection and characterization of circulating MM cells may address these issues. Although MRD detection in the peripheral blood at the same sensitivity as in the BM may be challenging, the identification of patients who do not achieve MRD negativity might reduce the need for BM biopsies. Here, we give an overview of approaches that have been described to detect and characterize MM cells when they occur at very low frequencies in the peripheral blood or in the BM, emphasizing recently described next-generation sequencing approaches for more comprehensive characterization of circulating MM cells.

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Section: Identification and Enumeration Of Cmmcs By Flow Cytometrymentioning

confidence: 99%

Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease

Waldschmidt

Anand

Knoechel

et al. 2018

Seminars in Hematology

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“…The use of therapeutic mAbs may also affect laboratory diagnostics in MM patients. It has been reported that DARA interferes with PCs detection by flow cytometry [ 22 ] and disturbs the detection and quantitation of M-protein by immunofixation electrophoresis (IFE) [ 23 ].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

Storti

Costa

Marchica

et al. 2020

JCM

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The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients.

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“…It is conceivable that the active site cleft of CD38 faces the plasma membrane and therefore is not easily accessible to antibodies or nanobodies. Some of the nanobodies have been shown to effectively target CD38 on human tumor cells in a mouse Xenograft model ( Fumey et al, 2017 ) and some of these nanobodies bind independently of daratumumab and isatuximab and may, therefore, be useful for detecting cell surface CD38 in daratumumab- and isatuximab-treated patients ( Oberle et al, 2017 ).…”

Section: Nucleotide Metabolizing Ecto-enzymes As Target For Nanobodiementioning

confidence: 99%

“…Fluorochrome-conjugated nanobodies, for example, are well suited for flow cytometry, microscopy, and molecular imaging applications ( Fumey et al, 2017 ). For example, nanobody JK36 recognizes a non-overlapping epitope on CD38 and can therefore detect cell surface CD38 by flow cytometry even in patients under treatment with daratumumab – where occupancy of CD38 by daratumumab prevents binding of most commercial diagnostic mAbs ( Oberle et al, 2017 ). Owing to their small size, fluorochrome-conjugated nanobodies often provide much higher resolution images in fluorescence microscopy than conventional antibodies ( Pleiner et al, 2015 ).…”

Section: Advantages and Limitations Of Nanobody-based Biologics In Pumentioning

confidence: 99%

Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity

et al. 2018

Self Cite

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Adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) are released as danger signals from cells during infection and sterile inflammation. In the extracellular compartment ATP is converted by CD39, CD73, and other ecto-enzymes into metabolites that modulate the activity of T cells and macrophages. While ATP mediates pro-inflammatory signals via P2X7 and other P2 receptors, adenosine triggers anti-inflammatory signaling via the adenosine 2a receptor (Adora2a) and other P1 receptors. The latter also plays a role in maintaining an immunosuppressive tumor microenvironment. NAD+ is converted by CD38, CD203 and other ecto-enzymes to the Ca2+ mobilizing messengers cyclic ADP-ribose and ADP-ribose, and to adenosine. Recent findings on the roles of CD38, CD39, CD73, CD203, P2X7, and Adora2a in inflammation and immunity underscore the potential of these proteins as drug targets. However, available small molecule inhibitors often lack specificity and mediate unwanted off-target toxicity. Nanobodies – single domain antibodies derived from heavy chain antibodies that naturally occur in camelids – display a propensity to bind functional epitopes not accessible to conventional antibodies. Like conventional antibodies, nanobodies and nanobody-based biologics are highly specific and have well-understood, tunable in vivo pharmacodynamics with little if any toxicity. Nanobodies thus represent attractive alternatives to small molecule inhibitors for modulating purinergic signaling in inflammation and immunity. Here we review recent progress made in developing nanobodies against key targets of purinergic signaling.

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Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection

Cited by 53 publications

References 14 publications

Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease

Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease

Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity

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