Comparison of CD38 antibodies &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;ex vivo&lt;/i&gt; mechanisms of action in multiple myeloma

Kinder, Michelle; Bahlis, Nizar J.; Malavasi, Fabio; Goeij, Bart E.C.G. de; Babich, Alexander; Sendecki, Jocelyn; Rusbuldt, Joshua; Bellew, Kevin M.; Kane, Colleen; Donk, Niels W.C.J. van de

doi:10.3324/haematol.2020.268656

Cited by 20 publications

(31 citation statements)

References 13 publications

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“… 36 This may be explained by the partly overlapping mode of action. 37,38 As a result of the similarities between both antibodies, it is unlikely that the combination of isatuximab and ATRA will be able to reverse daratumumab resistance.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of daratumumab combined with all-transretinoic acid in relapsed/refractory multiple myeloma

et al. 2021

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The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of daratumumab combined with all-transretinoic acid in relapsed/refractory multiple myeloma

et al. 2021

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“…The direct MM cell-killing effect of isatuximab has since been shown to depend on both caspase-dependent and, to a greater extent, lysosomal cell-death pathways [ 29 ]. Recent studies confirmed that daratumumab lacks the ability to induce apoptosis in the absence of crosslinking agents, though the contribution of direct cell death to overall anti-CD38 killing of MM cells in patients remains to be fully characterized [ 28 ].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

et al. 2022

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CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

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“…Naked CD38-targeting antibodies (approved: daratumumab and isatuximab; in clinical development: MOR202, SAR442085, and TAK-079) induce MM cell death via direct on-tumor effects such as the direct induction of apoptosis, complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) (Figure 1) [1][2][3]. Although there is overlap in the mode of action of these antibodies, there are also some differences [3]. Daratumumab is most potent in terms of the induction of CDC, while isatuximab is more effective in the direct induction of cell death [3].…”

Section: Naked Antibodies 21 Cd38-targeting Antibodiesmentioning

confidence: 99%

“…Although there is overlap in the mode of action of these antibodies, there are also some differences [3]. Daratumumab is most potent in terms of the induction of CDC, while isatuximab is more effective in the direct induction of cell death [3]. In addition, CD38-targeting antibodies have T cell stimulatory properties by eliminating CD38-positive regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells [4][5][6][7].…”

Section: Naked Antibodies 21 Cd38-targeting Antibodiesmentioning

confidence: 99%

Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

Verkleij¹,

Bruins²,

Donk³

2021

Hemato

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In the 2010s, immunotherapy revolutionized the treatment landscape of multiple myeloma. CD38-targeting antibodies were initially applied as monotherapy in end-stage patients, but are now also approved by EMA/FDA in combination with standards-of-care in newly diagnosed disease or in patients with early relapse. The approved SLAMF7-targeting antibody can also be successfully combined with lenalidomide or pomalidomide in relapsed/refractory myeloma. Although this has resulted in improved clinical outcomes, there remains a high unmet need in patients who become refractory to immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies. Several new antibody formats, such as antibody–drug conjugates (e.g., belantamab mafodotin, which was approved in 2020 and targets BCMA) and T cell redirecting bispecific antibodies (e.g., teclistamab, talquetamab, cevostamab, AMG-420, and CC-93269) are active in these triple-class refractory patients. Based on their promising efficacy, it is expected that these new antibody formats will also be combined with other agents in earlier disease settings.

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Comparison of CD38 antibodies <i>in vitro</i> and <i>ex vivo</i> mechanisms of action in multiple myeloma

Abstract: Not available.

Cited by 20 publications

References 13 publications

Efficacy and safety of daratumumab combined with all-transretinoic acid in relapsed/refractory multiple myeloma

Efficacy and safety of daratumumab combined with all-transretinoic acid in relapsed/refractory multiple myeloma

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Immunotherapy with Antibodies in Multiple Myeloma: Monoclonals, Bispecifics, and Immunoconjugates

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