α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

Teiluf, Katharina; Seidl, Christof; Blechert, Birgit; Gaertner, Florian; Gilbertz, Klaus-Peter; Fernández, Vanesa; Bassermann, Florian; Endell, Jan; Boxhammer, Rainer; Leclair, Stéphane; Vallon, Mario; Aichler, Michaela; Feuchtinger, Annette; Bruchertseifer, Frank; Morgenstern, Alfred; Essler, Markus

doi:10.18632/oncotarget.2986

Cited by 43 publications

(40 citation statements)

References 40 publications

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“…87 Compared to immunotoxins fewer results are available for anti-CD38 bispecific antibodies, however, the findings obtained so far look promising. For example, Flavell and coworkers investigated the effectiveness of two different bispecific antibodies, which were based on the OKT10 anti-CD38 antibody, for delivering the ribosome-inactivating protein (RIP) saporin to human T-ALL cell lines.…”

Section: Anti-cd38 Immunotoxins and Bispecifc Antibodies For The Treamentioning

confidence: 99%

Immunotherapies targeting CD38 in Multiple Myeloma

et al. 2016

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Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells.

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Section: Anti-cd38 Immunotoxins and Bispecifc Antibodies For The Treamentioning

confidence: 99%

Immunotherapies targeting CD38 in Multiple Myeloma

et al. 2016

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“…Daratumumab has been combined with different radionuclides (e.g., actinium-225), resulting in an increased tumoricidal effect besides its Fc-effector functions in preclinical models [131]. Bispecific pretargeted radiolabeled antibodies showed an even greater biodistribution to tumor cells and, in future, can represent an appealing approach for the treatment of MM, especially for heavily pretreated patients who usually remain sensitive to radiation [132]. Regarding the use of mAbs, another field of interest is the use of radiolabeled antibodies for imaging assessment with immuno-positron emission tomography (immuno-PET) [133].…”

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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“…In the future, radiolabeled daratumumab might be very interesting; preclinical data is promising and treatment with daratumumab is well-tolerated with encouraging results [36, 37]. Also, anti-CD138 might be a promising approach [38].…”

Section: Discussionmentioning

confidence: 99%

“…Use of radio-labeled anti-CD38 could be a promising approach not only for diagnostic purposes and treatment monitoring, but it might also be used in the context of radio-immunotherapy due to the restricted expression of CD38 on normal tissues. Preclinical studies have already been performed in xenograft mice models with radio-immunoconjugates consisting of the α-emitter [213Bi] coupled to the anti-CD38 monoclonal antibody, with a significant targeting of CD38 [37]. …”

Section: Target Mechanism In Nuclear Imagingmentioning

confidence: 99%

Nuclear medicine imaging of multiple myeloma, particularly in the relapsed setting

Waal

Glaudemans

Schröder

et al. 2016

Eur J Nucl Med Mol Imaging

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Multiple myeloma (MM) is characterized by a monoclonal plasma cell population in the bone marrow. Lytic lesions occur in up to 90 % of patients. For many years, whole-body X-ray (WBX) was the method of choice for detecting skeleton abnormalities. However, the value of WBX in relapsing disease is limited because lesions persist post-treatment, which restricts the capacity to distinguish between old, inactive skeletal lesions and new, active ones. Therefore, alternative techniques are necessary to visualize disease activity. Modern imaging techniques such as magnetic resonance imaging, positron emission tomography and computed tomography offer superior detection of myeloma bone disease and extramedullary manifestations. In particular, the properties of nuclear imaging enable the identification of disease activity by directly targeting the specific cellular properties of malignant plasma cells. In this review, an overview is provided of the effectiveness of radiopharmaceuticals that target metabolism, surface receptors and angiogenesis. The available literature data for commonly used nuclear imaging tracers, the promising first results of new tracers, and our pilot work indicate that a number of these radiopharmaceutical applications can be used effectively for staging and response monitoring of relapsing MM patients. Moreover, some tracers can potentially be used for radio immunotherapy.

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α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

Cited by 43 publications

References 40 publications

Immunotherapies targeting CD38 in Multiple Myeloma

Immunotherapies targeting CD38 in Multiple Myeloma

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

Nuclear medicine imaging of multiple myeloma, particularly in the relapsed setting

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