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Combining Milatuzumab with Bortezomib, Doxorubicin, Or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R

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Combining Milatuzumab with Bortezomib, Doxorubicin, Or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R CancerTherapy: Preclinical Combining Milatuzumab with Bortezomib, Doxorubicin, or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R. Smith,2 Susan Chen,1Maria Zalath,1and David M. Goldenberg1 Abstract Purpose: The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2. Experimental Design: Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM. Results: Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded sig- nificant antiproliferative effects in CD74+ cells.The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC50 of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-nB pathwayinCAGMMcells. In CAG-or KMS11-SCIDxenograftmodels ofdisseminated MM, milatuzumab more than doubled median survival time, compared withup to a 33% increase in median survival withbortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumabandbortezomibincreasedsurvivalsignificantlycomparedwitheither treatmentalone. Conclusions:The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are en- hanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically. Multiple myeloma (MM) is the second most prevalent blood transplantation is neither curative nor applicable to all patients cancer after non–Hodgkin lymphoma (1, 2). It represents and improved complete response rates have been seen in recent f1%of all cancers and 2%of all cancer deaths. Approximately clinical trials, the National Comprehensive Cancer Network 50,000 Americans currently have myeloma, and the American issued treatment guidelines recently that include recommenda- Cancer Society estimates 19,920 new cases of myeloma and tions for the use of newer treatment options for myeloma 10,690 deaths in 2008. Currently available therapies for patients. Lenalidomide and bortezomib regimens involving myeloma include chemotherapy and stem cell transplantation, combination therapy with doxorubicin and/or dexamethasone as well as new emerging therapies and combination therapy are now recommended in initial therapy protocols for regimens that are being tested in clinical trials (2, 3). High-dose transplant candidates and for treatment of relapsed/refractory melphalan followed by autologous stem cell transplantation is disease. Combination of melphalan and prednisone with currently the standard of care because of its high response rate thalidomide or bortezomib are recommended as initial therapy and relatively low morbidity and mortality. Because stem cell for nontransplant candidates. Thus, there has been consider- able progress in the field of myeloma therapy. Although cures have not been documented, molecular complete responses Authors’Affiliations: 1Garden State Cancer Center, Center for Molecular Medicine 2 have been achieved with some of the new therapies. However, and Immunology, Belleville, New Jersey and Fox Chase Cancer Center, relapses still occur after molecular complete response, usually Philadelphia, Pennsylvania Received 7/28/08; revised 12/24/08; accepted 1/12/09; published OnlineFirst after a longer period of event-free survival. 4/7/09. Despite the substantial progress, the unmet need for Grant support: USPHS grants P01-CA103985 and R01-CA109474 from the improved therapy of MM has led to the evaluation of cell National Cancer Institute, and grants from the Thomas and Agnes Carvel surface targets expressed by the myeloma cells. Although Foundation and the Walter and Louise Sutcliffe Foundation. The costs of publication of this article were defrayed in part by the payment of page antigens such as CD19 and CD20 are important targets for charges. This article must therefore be hereby marked advertisement in accordance non–Hodgkin lymphoma, they are expressed in only a with 18 U.S.C. Section 1734 solely to indicate this fact. minority of myeloma cases. In contrast, the cell surface protein Requests for reprints: Rhona Stein, Center for Molecular Medicine and CD74 is expressed at fairly high levels in nearly 90%of MM Immunology, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7012; clinical specimens but not on most normal human cells (4). In Fax: 973-844-7020; E-mail: [email protected]. F 2009 American Association for Cancer Research. addition, the humanized anti-CD74 monoclonal antibody, doi:10.1158/1078-0432.CCR-08-1953 milatuzumab (hLL1), has in vitro growth inhibitory effects on Clin Cancer Res 2009;15(8) April 15, 2009 2808 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Milatuzumab Improves Drug Therapy of Myeloma 2B8 (anti-CD20) was purified from hybridoma supernatant of cells ob- Translational Relevance tained from the American Type Culture Collection. B-B4 (anti-CD138) was purchased from BD Biosciences. The function of CD74 as a survival receptor, combined Immunophenotyping. Determination of antigen expression levels on with the expression of CD74 on malignant B cells and MM cells was done by indirect immunofluorescence assays using FITC- limited expression on normal tissues, implicate CD74 as a goat anti-mouse IgG, purchased from Invitrogen Corporation, as potential therapeutic target. Based on our previous preclin- described previously (9). All flow cytometry experiments were done and analyzed using a FACSCalibur (Becton Dickinson). ical studies, the anti-CD74 humanized monoclonal anti- In vitro 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium body, milatuzumab, is currently in clinical evaluation for bromide assay. The cytotoxicity assay was based on the method of therapy of multiple myeloma. In this article, we show the Mosmann (10). Briefly, cell lines were plated at 1 to 2 Â 104 cells per ability of milatuzumab to increase the efficacy of bortezo- well (100 AL) in 96-well plates, to which antibodies and/or drugs were mib, doxorubicin, and dexamethasone in multiple myeloma added (100 AL). After incubation for 4 d at 37jC in a humidified CO2 cell lines and animal models. The results presented here (5%) incubator, 25 AL of 5.0 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5- now suggest testing these combinations clinically, with diphenyltetrazolium bromide (MTT) were added, and the cells were the goal of improving the outcome for patients with multi- incubated for an additional 4 h at 37jC. Plates were then centrifuged A ple myeloma. and supernatants were removed. Pellets were dissolved using 100 L DMSO per well and absorbance was measured at 570 nm on a microplate reader (Molecular Devices). Because unlabeled milatuzu- mab was reported previously to require cross-linking for cytotoxic MM cell lines and therapeutic effects in MM models (5, 6). activity (6), goat anti-human IgG (GAH) was added to some of the Based on these preclinical studies, milatuzumab is currently in wells. Milatuzumab was used at a final concentration of 5 Ag/mL and A clinical evaluation for therapy of MM. Here, we provide in vitro GAH was used at 20 g/mL. Percent growth inhibition and IC50 values and in vivo data corroborating the therapeutic efficacy of were determined using 4 replicates. milatuzumab in human MM model systems and expand our DNA fragmentation. Flow cytometric analysis of cellular DNA was observations to show that this monoclonal antibody is more done after propidium iodide staining (11, 12). Cells were placed in 24- Â 5 effective than key therapeutic agents for MM treatment, well plates (1.5 to 3 10 cells per well) and treated with drugs (at concentrations indicated for each experiment) or mAbs (5 Ag/mL) in including bortezomib, doxorubicin, and dexamethasone, when the presence or absence of a second antibody (20 Ag/mL). Percent each agent is given alone. In addition, the efficacies of the apoptotic cells (hypodiploid cells) was determined after a chemotherapeutics are enhanced when given in combination 48-h incubation. with milatuzumab. Cleaved caspase-3. Cells were incubated in the presence or absence of the drugs (at concentrations indicated for each experiment) and/or mAbs for 48 h. Changes in the intracellular levels of cleaved caspase-3 were measured using FITC-conjugated rabbit antiactivated caspase-3 Materials and Methods (BD Bioscience) as per the manufacturer’s directions. Analyses were done on the FACSCalibur. Cells. The cell lines were obtained as follows: KMS11 and KMS12- Western blots. Cells were cultured in the presence or absence of the PE from Dr. T. Otsuki (Kawasaki Medical School, Okayama, Japan), mAbs and/or drugs for the indicated times, pelleted, washed thrice in CAG from Dr. Joshua Epstein (University of Arkansas, Fayetteville, AR), PBS, then lysed in ice cold radioimmunoprecipitation assay buffer and OPM-2 from Dr.
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