The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Moreno, Laura; Pérez, Cristina Fernández; Zabaleta, Aintzane; Manrique, Irene; Alignani, Diego; Ajona, Daniel; Blanco, Laura; Lasa, Marta; Maiso, Patricia; Rodríguez, Idoia; Gárate, Sonia; Jelı́nek, Tomáš; Segura, Víctor; Moreno, Cristina; Merino, Juana; Rodríguez‐Otero, Paula; Panizo, Carlos; Prósper, Felipe; Miguel, Jesús F. San; Paiva, Bruno

doi:10.1158/1078-0432.ccr-18-1597

Cited by 171 publications

(178 citation statements)

References 45 publications

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“…The antibody acts through a combination of mechanisms, which may depend on the expression level of the target. 39 EMA has accepted for review the MAA for isatuximab for the treatment of relapsed/refractory multiple myeloma (RRMM). 40 FDA has accepted a BLA for isatuximab as a treatment for patients with RRMM; the target action date for the FDA's decision is April 30, 2020.…”

Section: Isatuximab (Sanofi)mentioning

confidence: 99%

Antibodies to watch in 2020

Kaplon

Muralidharan²,

Schneider

et al. 2019

mAbs

412

296

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This 2020 installment of the annual 'Antibodies to Watch' series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry's clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future. *Note on key updates through December 18, 2019: 1) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 6; 2) the European Commission approved romosozumab on December 9, 2019; 3) the European Medicines Agency issued a positive opinion for brolucizumab; 4) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 5) GlaxoSmithKline submitted a BLA for belantamab mafodotin; and 6) the status of the Phase 3 study (NCT04128696) of GSK3359609, a humanized IgG4 anti-ICOS antibody, in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting. ARTICLE HISTORY

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Section: Isatuximab (Sanofi)mentioning

confidence: 99%

Antibodies to watch in 2020

Kaplon

Muralidharan²,

Schneider

et al. 2019

mAbs

412

296

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“…See related article by Moreno et al,p. 3176 In this issue of Clinical Cancer Research, Moreno and colleagues (1) provide an original analysis of the characteristics of a new chimeric anti-CD38 antibody candidate for multiple myeloma therapy.…”

Section: And Angelo Corso Fainimentioning

confidence: 99%

Mechanism of Action of a New Anti-CD38 Antibody: Enhancing Myeloma Immunotherapy

Malavasi

Faini

2019

Clinical Cancer Research

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Antibody therapy is a treatment option for several diseases, including multiple myeloma. The logic behind it is relatively simple: A target molecule is selected because of its expression on tumor cells, and the antibody delivers cytotoxic effects.Therapeutic results in multiple myeloma indicate that the anti-CD38 antibodies may have relevant immunotherapeutic properties.See related article by Moreno et al., p. 3176 In this issue of Clinical Cancer Research, Moreno and colleagues (1) provide an original analysis of the characteristics of a new chimeric anti-CD38 antibody candidate for multiple myeloma therapy.The initial promise of mAb, heralded as a "magic bullet" for cancer therapy, was not immediately fulfilled. Decades of frustrating results were necessary before the clinical success of anti-CD20 antibodies finally rewarded the efforts of clinicians and pharmaceutical companies, rekindling interest in pursuing the development of antibody-based therapies. This required rethinking the role of antibodies in vivo: it is now accepted that some antibodies block the function of a membrane receptor while others synergize it. Synergistic antibodies occupy a domain that hosts the site of the natural ligand of the molecule (molecular mimicry). When the target lies in close proximity to professional receptors, it can trigger signals (molecular parasitism). CD38, functionally associated with the B-cell receptor (BCR), the T-cell receptor (TCR), and CD16A (the low-affinity IgG FcR; ref.2), is one example.These conclusions are relatively straightforward when the function of the target molecule is known. However, such is not the case for CD38, whose precise roles are not yet fully known. The results of antibody therapy following the introduction of daratumumab (3) have provided useful practical and theoretical information about the functions of the target and, at the same time, revealed some unexpected mechanisms of action (MoA) of therapeutic antibodies in vivo. The findings presented by Moreno and colleagues indicate that isatuximab has unique characteristics, only some of which are shared with daratumumab. In fact, given their different MoAs, the two antibodies might be potentially valuable as therapeutic complements or alternatives in patients developing resistance to one of them. The particular benefit provided by isatuximab is its sensitivity to the number of CD38 molecules present on target cells. Isatuximab saturates membrane CD38 and can be internalized. However, antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) are triggered only when the number of surface CD38 molecules reaches a threshold. The same thing happens in the induction of direct apoptosis. Isatuximab does not alter the transcription on a high CD38 þ myeloma line.The existence of such a threshold was established by quantifying the number of CD38 molecules expressed both by multiple myeloma and by the majority of normal cell populations. Isatuximab may have a lower deple...

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“…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]. An intriguing way to overcome the acquired resistance derived from antigen downregulation could be the addition of molecules able to re-induce CD38 expression on cell surface, such as all-trans retinoic acid (ATRA) or panobinostat [127,128].…”

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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The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Cited by 171 publications

References 45 publications

Antibodies to watch in 2020

Antibodies to watch in 2020

Mechanism of Action of a New Anti-CD38 Antibody: Enhancing Myeloma Immunotherapy

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

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