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Distinct Apoptotic Signaling Characteristics of the Anti-CD40

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Distinct Apoptotic Signaling Characteristics of the Anti-CD40 Published OnlineFirst May 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0479 Clinical Cancer Cancer Therapy: Preclinical Research Distinct Apoptotic Signaling Characteristics of the Anti-CD40 Monoclonal Antibody Dacetuzumab and Rituximab Produce Enhanced Antitumor Activity in Non-Hodgkin Lymphoma Timothy S. Lewis1, Renee S. McCormick1, Kim Emmerton1, Jeffrey T. Lau3, Shang-Fan Yu3, Julie A. McEarchern2, Iqbal S. Grewal1, and Che-Leung Law1 Abstract Purpose: Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40). Experimental Design: Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated–cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells. Results: The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P ¼ 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell- proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregu- lated BCL-6 oncoprotein in a cell line–specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-xL. Conclusions: Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combina- tion. Clin Cancer Res; 17(14); 4672–81. Ó2011 AACR. Introduction lymphoma (DLBCL), whereas follicular lymphoma (FL) is the most common subtype of indolent lymphoma. Target- Non-Hodgkin lymphoma (NHL) is a heterogeneous ing lymphomas with monoclonal antibodies has proven to group of B-cell malignancies with a considerable amount be a productive therapeutic approach, and monoclonal of genetic diversity, reflecting the differentiation status at antibodies specific for CD20, CD22, CD23, CD30, the time of lymphocyte transformation (1). The majority of CD40, CD52, CD74, CD80, TRAIL, and VEGF are currently NHL cases are classified as aggressive diffuse large B-cell being tested in the clinic as unconjugated antibodies, anti- body drug conjugates, or radioimmunotherapies (2, 3). The anti-CD20 monoclonal antibody, rituximab, was the Authors' Affiliations: Departments of 1Pre-Clinical Research and first of these to receive regulatory approval, and has sig- 2Experimental Therapeutics, Seattle Genetics, Inc., Bothell, Washington; nificantly improved treatment of NHL. Rituximab’s pri- and 3Department of Translational Oncology, Genentech Inc., South San mary mechanism of action is effector function-based, and it Francisco, California is able to mediate antibody dependent cellular cytotoxicity Note: Supplementary data for this article are available at Clinical Cancer (ADCC), complement dependent cytotoxicity (CDC), and Research Online (http://clincancerres.aacrjournals.org/). antibody dependent cellular phagocytosis (ADCP) (4). In Corresponding Author: Timothy S. Lewis, Department of Pre-Clinical Research, Seattle Genetics, Inc., 21823–30th Drive Southeast, Bothell, addition to effector function activity, rituximab is a signal- WA 98021 U.S.A. Phone: 425-527-4668; Fax: 425-527-4609; E-mail: ing antibody capable of suppressing antiapopototic path- [email protected] ways and chemosensitizing drug-resistant NHL cells (5–7). doi: 10.1158/1078-0432.CCR-11-0479 In the treatment of NHL, rituximab is used either as a Ó2011 American Association for Cancer Research. monotherapy or in combination with chemotherapy such 4672 Clin Cancer Res; 17(14) July 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst May 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0479 Dacetuzumab Enhances the Antitumor Activity of Rituximab Translational Relevance The humanized anti-CD40 monoclonal antibody, dacetuzumab (SGN-40), has antiproliferative and apop- This study evaluates the potential benefit of combin- totic activity against a panel of high-grade B-lymphoma ing the CD40-targeting monoclonal antibody dacetu- cell lines (23). Dacetuzumab initiates signaling in lym- zumab with rituximab in the treatment of non-Hodgkin phoma cells following binding to CD40, activating the lymphoma (NHL). Dacetuzumab mediates effector ERK1/2, JNK, p38 MAP kinase, and NF-kBsignaltrans- function (ADCC and ADCP), but also activates anti- duction pathways (24). Constitutive activation of these proliferative and proapoptotic signaling on NHL cells. pathways downregulates B-cell lymphoma 6 (BCL-6) Dacetuzumab is currently being evaluated in clinical and c-Myc oncoproteins in lymphoma cell lines, trials for the treatment of NHL. In the present study, whereas the proapoptotic p53 family member TAp63a, dacetuzumab was shown to enhance the antitumor Fas, and Bim are upregulated (24). In addition, dace- activity of rituximab in NHL cell line and xenograft tuzumab is an IgG1 antibody capable of mediating models. Both rituximab and dacetuzumab activated antibody-dependent cellular cytotoxicity (ADCC) and MAP kinase signaling and downregulated BCL-6 onco- antibody-dependent cellular phagocytosis (ADCP) effec- protein, which is frequently translocated and hypermu- tor function activities (23, 25). Dacetuzumab does not tated in NHL. Dacetuzumab alone upregulated the mediate CDC. proapoptotic p53 family member TAp63a, a suppressor The mechanisms of action of rituximab and dacetuzu- of tumorigenesis. Rituximab and dacetuzumab signal- mab have not been contrasted, and the potential to ing had inverse effects on the expression of Fas and BCL- improve rituximab’s activity in NHL with an antibody xL. Our data suggest that antibody-mediated signaling targeting CD40 has not been explored. In this study, we through both CD20 and CD40 may be an effective examined the signaling and effector function character- strategy in the treatment of NHL. istics of dacetuzumab and rituximab alone and in com- bination. Combination index analysis determined that dacetuzumab is additive to synergistic with rituximab in NHL cell lines in an in vitro proliferation assay. Further- as cyclophosphamide, doxorubicin, vincristine, and pre- more, we found that dacetuzumab improved the anti- dnisone (CHOP) for DLBCL treatment or cyclophos- tumor activity of rituximab in a xenograft model of NHL. phamide, vincristine, prednisone (CVP) for follicular The combined antitumor activity of these two antibodies lymphoma (8–10). in vitro was not due to enhanced effector function, rather Whereas response rates for rituximab-based therapies are the relative ability of these antibodies to activate apopto- high in NHL, some patients are refractory to rituximab and tic signaling pathways correlated with potency. Both relapse following treatment is common, particularly in dacetuzumab and rituximab were found to negatively indolent lymphoma (11). Resistance to rituximab has been regulate the prosurvival BCL-6 oncoprotein in a cell linked to overexpression of the complement inhibitor line–specific manner; however, only dacetuzumab upre- CD59 and the antiapoptotic proteins Bcl-XL and Ying Yang gulated the proapoptotic p53 family member TAp63a 1 (YY1) (12). Downregulation of CD20 expression has also and Fas death receptor. The differential apoptotic signal- been reported in B-cell lymphomas following treatment ing characteristics of dacetuzumab and rituximab are with rituximab combination therapies (13). This unmet likely to be significant to the activity of this antibody medical need warrants the development of therapeutic combination in NHL. antibodies targeting other lymphoma cell surface antigens to supplement current NHL therapeutic regimens. Materials and Methods The tumor necrosis factor (TNF) receptor superfamily member, CD40, is continually expressed on developing B- Cell culture cells from the pro-B phase through differentiation into Raji, Ramos, RL, SU-DHL-4, and WIL2-S lymphoma cell memory B-cells and plasma cells (14, 15). CD40 is also lines were obtained from American Type Culture Collec- expressed on a variety of cells types other than lympho- tion and cultured in RPMI 1640 media supplemented with cytes, including dendritic cells, monocytes, and macro- 10% fetal bovine serum. phages. The disease expression profile of CD40 is broader than that of CD20, and includes NHL, Hodgkin Non-Hodgkin lymphoma in vivo studies lymphoma, multiple myeloma, acute lymphoblastic leu- Severe combined immunodeficient mice (SCID) mice kemia, and numerous carcinomas (16–19). Binding of were subcutaneously implanted with 5 Â 106 Ramos CD40 to its ligand (CD40L)
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