Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Caserta, Enrico; Chea, Junie; Minnix, Megan; Poku, Erasmus; Viola, Domenico; Vonderfecht, Steven; Yazaki, Paul J.; Crow, Desiree; Khalife, Jihane; Sanchez, James F.; Palmer, Joycelynne; Song, Hui; Carlesso, Nadia; Keats, Jonathan J.; Kim, Young; Buettner, Ralf; Marcucci, Guido; Rosen, Steven T.; Shively, John E.; Colcher, David; Krishnan, Amrita; Pichiorri, Flavia

doi:10.1182/blood-2017-09-807263

Cited by 56 publications

(53 citation statements)

References 25 publications

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“…Here, we show that the CD38/Dara complex can be rapidly internalized in MM cells, and, although it is not certain how internalization process affects anti-neoplastic efficacy, we believe it may have contributed to positive results obtained when Dara was used for imaging studies. [41][42][43] There have been several reports that end-stage MM patients are now more likely to have extramedullary disease after becoming resistant to combinations of IMiDs, proteasome inhibitors, and CD38 antibody combinations. 44 Clearly, clones that are more resistant to Dara combination treatments are often independent of the BM-ME, 45 and one could extrapolate from our study that prolonged Dara exposure may support resistance.…”

Section: Discussionmentioning

confidence: 99%

Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

et al. 2018

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Daratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells in vitro and in vivo, independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

et al. 2018

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“…Indeed, surface antigens expressed on myeloma cells could be a target for radiolabeled mAbs, which would allow highly specific tumor detection and precise response assessment. Daratumumab has already been labeled to different positron emitters showing excellent targeting in preclinical models [134][135][136]. With these premises, immuno-PET could represent a useful tool for imaging assessment and also for guiding treatment strategies, as this technique could potentially be used to predict the effectiveness of mAb therapy.…”

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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“…Optimal dosing could even be achieved through sequential imaging. It is true, however, that immunoPET is still in its early stages in MM and that only preclinical data or data reported in small patient samples have been published [84][85][86][87][88]. Nevertheless, there is evidence to suggest that, once exploited, this imaging can have a significant impact on the management of MM patients.…”

Section: Now What?mentioning

confidence: 99%

“…Mice bearing subcutaneous MM tumours were imaged using 64Copper-labelled anti-CD38 mAbs with and without a dose of unlabelled mAbs (Figure 1). teams have begun to take an interest in this issue in preclinical studies, including ours [84,85,88,95], and a small first-in-human study was very recently published [88]. Anti-CD38 immunoPET has a high potential in selecting patients and optimal conditions for daratumumab-based treatment.…”

Section: Now What?mentioning

confidence: 99%

ImmunoPET in Multiple Myeloma—What? So What? Now What?

Bailly

Chalopin

Gouard

et al. 2020

Cancers

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Despite constant progress over the past three decades, multiple myeloma (MM) is still an incurable disease, and the identification of new biomarkers to better select patients and adapt therapy is more relevant than ever. Recently, the introduction of therapeutic monoclonal antibodies (mAbs) (including direct-targeting mAbs and immune checkpoint inhibitors) appears to have changed the paradigm of MM management, emphasizing the opportunity to cure MM patients through an immunotherapeutic approach. In this context, immuno-positron emission tomography (immunoPET), combining the high sensitivity and resolution of a PET camera with the specificity of a radiolabelled mAb, holds the capability to cement this new treatment paradigm for MM patients. It has the potential to non-invasively monitor the distribution of therapeutic antibodies or directly monitor biomarkers on MM cells, and to allow direct observation of potential changes over time and in response to various therapeutic interventions. Tumor response could, in the future, be anticipated more effectively to provide individualized treatment plans tailored to patients according to their unique imaging signatures. This work explores the important role played by immunotherapeutics in the management of MM, and focuses on some of the challenges for this drug class and the significant interest of companion imaging agents such as immunoPET.

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Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Cited by 56 publications

References 25 publications

Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

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

ImmunoPET in Multiple Myeloma—What? So What? Now What?

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