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The Mechanism of Action of the Anti-CD38 Monoclonal Antibody

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The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Published OnlineFirst January 28, 2019; DOI: 10.1158/1078-0432.CCR-18-1597 Translational Cancer Mechanisms and Therapy Clinical Cancer Research The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma Laura Moreno1, Cristina Perez1, Aintzane Zabaleta1, Irene Manrique1, Diego Alignani1, Daniel Ajona1,2,3, Laura Blanco1, Marta Lasa1, Patricia Maiso1, Idoia Rodriguez1, Sonia Garate1, Tomas Jelinek1, Victor Segura1, Cristina Moreno1, Juana Merino1, Paula Rodriguez-Otero1, Carlos Panizo1, Felipe Prosper1, Jesus F. San-Miguel1, and Bruno Paiva1 Abstract Purpose: Knowledge about the mechanism of action (MoA) triggered by CD38lo and CD38hi tumor plasma cells (PC), of monoclonal antibodies (mAb) is required to understand (iv) antibody-dependent cellular phagocytosis (ADCP) was which patients with multiple myeloma (MM) benefit the most triggered only by CD38hi MM cells, whereas (v) complement- from a given mAb, alone or in combination therapy. Although dependent cytotoxicity could be triggered in less than half of there is considerable research about daratumumab, knowl- the patient samples (those with elevated levels of CD38). edge about other anti-CD38 mAbs remains scarce. Furthermore, we showed that isatuximab depletes CD38hi Experimental Design: We performed a comprehensive B-lymphocyte precursors and natural killer (NK) lymphocytes analysis of the MoA of isatuximab. ex vivo—the latter through activation followed by exhaustion Results: Isatuximab induces internalization of CD38 but and eventually phagocytosis. not its significant release from MM cell surface. In addition, we Conclusions: This study provides a framework to under- uncovered an association between levels of CD38 expression stand response determinants in patients treated with isatux- and different MoA: (i) Isatuximab was unable to induce direct imab based on the number of MoA triggered by CD38 levels apoptosis on MM cells with CD38 levels closer to those in of expression, and for the design of effective combinations patients with MM, (ii) isatuximab sensitized CD38hi MM cells aimed at capitalizing disrupted tumor–stroma cell protection, to bortezomib plus dexamethasone in the presence of stroma, augmenting NK lymphocyte–mediated ADCC, or facilitating (iii) antibody-dependent cellular cytotoxicity (ADCC) was ADCP in CD38lo MM patients. Introduction cancer immunotherapy, monoclonal antibodies (mAb) are at Growing knowledge about tumor and immune cell biology the forefront of recent clinical development with two new drugs led to continuous development of immunotherapies against approved in 2015 for the treatment of relapsed/refractory each of the four major nodes of vulnerability in the cancer– disease (2). immune relationship: direct targeting of surface antigens; Characteristics that make antigens attractive as targets for mAb- boosting of numbers and functioning of immune effectors; based therapy include, amongst others, the density of expression activating tumor antigen-specific immunity, and; overcoming of the target molecule by malignant and benign cells (3). Other inhibitory immune suppression (1). Multiple myeloma (MM) desirable characteristics of target tumor antigens vary depending is no exception to this; however, among the four major nodes of on the mAb construct and the mechanism of action (MoA) triggered by such constructs (3). Some mAbs that target antigens on the surface of malignant cells can induce apoptosis by direct 1Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada transmembrane signaling (4). There is also evidence that mAbs (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC kill target cells by complement-dependent cytotoxicity (CDC; number CB16/12/00369 and CB16/12/00489, Pamplona, Spain. 2Solid Tumors ref. 5), or by inducing antibody-dependent cellular cytotoxicity Program, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/ (ADCC; ref. 6) and phagocytosis (ADCP; ref. 7). Thus, exquisite 00443, Pamplona, Spain. 3Department of Biochemistry and Genetics, School understanding about the MoA of novel mAbs is warranted, of Sciences, University of Navarra, Pamplona, Spain. because precise identification of the (one or more) effector Note: Supplementary data for this article are available at Clinical Cancer mechanisms triggered by these can have considerable impact on Research Online (http://clincancerres.aacrjournals.org/). optimal selection of patients' candidates to receive a given mAb based on tumor phenotypes, the design of effective treatment L. Moreno, C. Perez, and A. Zabaleta contributed equally to this work. combinations, and correct immune monitoring to predict treat- Corresponding Author: Bruno Paiva, CIMA, Avda. Pio XII 55, 31008 Pamplona, ment failure (i.e., precision medicine). Navarra. Phone: 349-4919-4700, ext. 1038; E-mail: [email protected] CD38 is a type II transmembrane glycoprotein without an doi: 10.1158/1078-0432.CCR-18-1597 internal signaling domain that, although at variable levels (8), Ó2019 American Association for Cancer Research is expressed on malignant plasma cells (PC) from all patients with www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 28, 2019; DOI: 10.1158/1078-0432.CCR-18-1597 Moreno et al. informed consent was given by each patient, according to the Translational Relevance local ethics committee and the Helsinki Declaration. We used the Greater knowledge about the immune effector mechanisms RPMI-8226, MM1S, OPM2, and H929 MM cell lines for studying of monoclonal antibodies is a prerequisite for better predic- internalization or release of CD38 after isatuximab binding. The tion of patients' response and optimal monitoring of treat- effect of isatuximab on proliferation and apoptosis was measured ment effects. Here, we performed a comprehensive analysis using diphenyltetrazolium bromide (MTT) and flow cytometry about the mechanism of action of isatuximab in multiple assays, whereas the ability of isatuximab to trigger CDC, ADCP myeloma. Our results underline similarities and differences and ADCC was determined using various flow cytometry meth- between isatuximab and other anti-CD38 monoclonal anti- ods. In parallel, we evaluated the immune modulatory effects of bodies and unveiled a direct association between the levels of isatuximab in the series of patients described above, and purified CD38 expression and the mechanisms triggered by isatuxi- NK lymphocytes from healthy individuals to understand the mab; accordingly, antibody-dependent cellular cytotoxicity mechanisms behind their activation and depletion after treatment emerges as the most prevalent effector mechanism by which with isatuximab, using fluorescence-activated cell sorting (FACS) isatuximab eliminates tumor cells. They also provide informa- and gene expression profiling (GEP). We also evaluated isatux- À/À tion that could explain, at least in part, why patients with lower imab MoA in NOD/scid/gc (NSG) xenotransplant models, expression of CD38 may respond poorly to these drugs than which were inoculated with firefly luciferase-expressing MM1S patients with higher CD38 expression. We also provide new cells in the presence or absence of immune effector cells [i.e., insight about the paradoxical depletion of natural killer (NK) peripheral blood mononucleated cells (PBMC) obtained from lymphocytes following treatment with anti-CD38 monoclonal healthy donors]. We examined the potential of an anti-CD137 antibodies; further development of therapeutic strategies to mAb, lenalidomide and bortezomib to enhance isatuximab- overcome this phenomenon should become a priority. mediated activation of NK lymphocytes and prevent their exhaus- tion, using flow cytometry methods. The Wilcoxon signed rank test was used to evaluate the statis- tical significance of the differences observed between CD16 mean MM (9). CD38 mAbs currently available or being developed for the fluorescence intensity (MFI) levels of NK lymphocytes untreated treatment of MM include daratumumab, isatuximab, MOR202, versus treated with isatuximab, whereas the Mann–Whitney U and Ab19. Except the latter, all other three mAbs are under clinical and the Kruskal–Wallis tests were used to estimate the statistical development but, so far, only daratumumab has been approved significance of differences observed between two or more groups, for the treatment of patients with MM. Coincidently, the MoA of respectively. Correlation studies were performed using the Pear- daratumumab has been considerably investigated and several son test. Survival curves were plotted according to the Kaplan– effector mechanisms were identified: tumor cell apoptosis upon Meier method and compared using the log-rank test. The SPSS FcgR cross-linking (10), CDC (11), ADCP (12), and ADCC (13). software (version 20.0; SPSS Inc.) was used for all statistical tests. More recently, Krejcik and colleagues (14, 15) have shown that þ daratumumab depletes CD38 ve immune regulatory cells, which promoted the expansion of TCR-related T lymphocytes. Although Results these findings are surprising because they suggest that daratumu- Isatuximab induces internalization of CD38 but not its mab is capable of depleting cells with considerable lower levels of significant release from MM cell surface CD38, they also indicate that drugs able to enhance the immune Recent evidence indicates that
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