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Targeting the Lymphotoxin-B Receptor with Agonist Antibodies As a Potential Cancer Therapy

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Targeting the Lymphotoxin-B Receptor with Agonist Antibodies As a Potential Cancer Therapy Research Article Targeting the Lymphotoxin-B Receptor with Agonist Antibodies as a Potential Cancer Therapy Matvey Lukashev,1 Doreen LePage,1 Cheryl Wilson,1 Ve´ronique Bailly,1 Ellen Garber,1 AlexLukashin, 1 Apinya Ngam-ek,1 Weike Zeng,1 Norman Allaire,1 Steve Perrin,1 Xianghong Xu,1 Kendall Szeliga,1 Kathleen Wortham,1 Rebecca Kelly,1 Cindy Bottiglio,1 Jane Ding,1 Linda Griffith,1 Glenna Heaney,1 Erika Silverio,1 William Yang,1 Matt Jarpe,1 Stephen Fawell,1 Mitchell Reff,1 Amie Carmillo,1 Konrad Miatkowski,1 Joseph Amatucci,1 Thomas Crowell,1 Holly Prentice,1 Werner Meier, 1 Shelia M. Violette,1 Fabienne Mackay,1 Dajun Yang,2 Robert Hoffman,3 and Jeffrey L. Browning1 1Departments of Immunobiology, Oncopharmacology, Molecular Engineering, Molecular Profiling, Molecular Discovery, Antibody Humanization, and Cellular Engineering, Biogen Idec, Cambridge, Massachusetts; 2Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; and 3AntiCancer, Inc., San Diego, California Abstract receptor (TRAILR) 1/2, death receptor (DR) 3, DR6, and possibly ectodermal dysplasia receptor (EDAR). These TNFRs harbor The lymphotoxin-B receptor (LTBR) is a tumor necrosis factor signaling adaptor motifs termed death domains that can initiate receptor family member critical for the development and the extrinsic apoptosis program. In addition, TNFRs of this group maintenance of various lymphoid microenvironments. Herein, can exert antitumor effects via other mechanisms that include we show that agonistic anti-LTBR monoclonal antibody (mAb) tumor sensitization to chemotherapeutic agents, activation of CBE11 inhibited tumor growth in xenograft models and antitumor immunity, and disruption of tumor-associated micro- potentiated tumor responses to chemotherapeutic agents. vasculature (1, 2). The therapeutic potential of TNFR agonists has In a syngeneic colon carcinoma tumor model, treatment of been well documented in many preclinical studies; however, the tumor-bearing mice with an agonistic antibody against excluding the current TRAILR-based therapies, clinical develop- murine LTBR caused increased lymphocyte infiltration and ment of TNF and other death receptor agonists has been hampered necrosis of the tumor. Apattern of differential gene expres- by the danger of nonspecific cytotoxicity, vascular activation, and sion predictive of cellular and xenograft response to LTBR inflammation. activation was identified in a panel of colon carcinoma cell The TNFR family also includes several members, including lines and when applied to a panel of clinical colorectal tumor lymphotoxin-h receptor (LThR), RANK, and EDAR, which regulate samples indicated 35% likelihood a tumor response to CBE11. developmental programs in lymph nodes, hair follicles, teeth, bone, Consistent with this estimate, CBE11 decreased tumor size and mammary epithelium (3–5). Signaling through these receptors and/or improved long-term animal survival with two may offer novel means for therapeutic modulation of tumors via of six independent orthotopic xenografts prepared from B signals that control cellular proliferation, survival, and differenti- surgical colorectal carcinoma samples. Targeting of LT R ation. In addition, LThR, CD27, CD30, CD40, 41BB, OX40, HVEM, with agonistic mAbs offers a novel approach to the treatment RANK, and others in this group serve immunoregulatory functions of colorectal and potentially other types of cancers. (Cancer that may stimulate tumor immunity (6). For example, activation of Res 2006; 66(19): 9617-24) CD40 inhibits the growth of hematopoietic and epithelial tumor cells and can promote antitumor immune responses (7). LThR Introduction plays a central role in the formation of lymphoid organs (3). During Receptors of the tumor necrosis factor (TNF) receptor (TNFR) lymph node development and in the mature system, LThR induces family have been pursued as attractive therapeutic targets in stromal cells to specialize leading to the expression of surface oncology since the early studies showing antitumor activities of adhesion molecules and the secretion of chemokines that attract TNF and later FAS/Apo-1 antibody (1, 2). TNFR1 and FAS belong to and position lymphocytes, thereby maintaining certain micro- h a group of cell death–inducing TNFRs that also includes nerve environments (8, 9). Likewise, LT R contributes to the morpho- growth factor receptor, TNF-related apoptosis-inducing ligand genesis of specialized epithelial cells termed M cells in the Peyer’s patches that develop from the stem cell compartment of the intestinal crypt (10, 11). Continual LThR signaling is also crucial for the specialization of the high endothelial vasculature in the Note: Supplementary data for this article are available at Cancer Research Online lymphoid organs (12). The lymphotoxin system is integrally (http://cancerres.aacrjournals.org/). involved in the formation of organized ectopic lymphoid structures M. Lukashev, D. LePage, C. Wilson, and V. Bailly contributed equally to this work. Current address for D. LePage: PharmaMar USA, Inc., Cambridge, Massachusetts; in chronically inflamed sites (13). These activities may be S. Fawell: Novartis Institutes for Biomedical Sciences, Cambridge, Massachusetts; important in the tumor microenvironment to facilitate immuno- F. Mackay: Department of Arthritis and Inflammation, Garvan Institute of Medical Research, Darlington, Australia; D. Yang: Ascenta Therapeutics, San Diego, California. logic involvement. Requests for reprints: Jeffrey L. Browning, Biogen Idec, 12 Cambridge Center, We have reported previously that LThR activation induced by Cambridge, MA 02142. Phone: 617-679-3312; Fax: 617-679-3148; E-mail: jeff.browning@ its ligand lymphotoxin-a/h or an agonistic monoclonal antibody biogenidec.com. I2006 American Association for Cancer Research. (mAb) triggers an IFN-g-dependent death in HT29 colon carci- doi:10.1158/0008-5472.CAN-06-0217 noma cells (14, 15). More recently, expression within a tumor of a www.aacrjournals.org 9617 Cancer Res 2006; 66: (19). October 1, 2006 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2006 American Association for Cancer Research. Cancer Research second ligand for LThR called LIGHT was able to trigger an sizes and log-rank analysis for the survival curves. All tumor studies were immunomediated tumor response (16, 17). Here, we show that an carried out in accordance with the respective institutional animal care agonistic anti-LThR mAb blocks tumor growth in models of colon committee protocols. and cervical carcinoma, including s.c. and orthotopic xenografts of Gene expression analysis. RNA from cultured cells or xenograft tumor samples was isolated by the standard Trizol protocol (Invitrogen, human colorectal tumors. These findings indicate that agonists of h Carlsbad, CA) followed by additional purification on RNeasy columns LT R may prove useful as treatments for malignant diseases. (Qiagen, Valencia, CA). Hybridization probes were prepared and hybridized to U95Av2 GeneChips according to the Affymetrix (Santa Clara, CA) protocols. Transcript profiles of the clinical colorectal tumor samples Materials and Methods were extracted from a commercially available data set (Gene Logic, Cell lines and reagents. The HT29 clone 14 was described previously Gaithersburg, MD) as U95A GeneChip data and converted to the U95Av2 (14). All other human cultured tumor lines and the murine CT26 colon format for further analysis. Signal intensity data were exported using MAS5 carcinoma line were obtained from the American Type Culture Collection software, filtered to remove genes marked as absent across all samples, and (ATCC) or the National Cancer Institute tumor cell line collection. imported for further analysis into GeneSpring (Agilent, Palo Alto, CA). Monoclonal antibodies, including the murine CBE11 and BDA8 anti-human Prediction of sensitivity to the LThR agonist mAb was done using the LThR, 1E6 anti-human LFA3 (all IgG1), and the hamster Ha4/8 anti-keyhole k-nearest neighbor class prediction algorithm implemented in the Gene- limpet hemocyanin and ACH6 anti-murine LThR mAbs, have been Spring gene expression analysis software (Agilent) on log-transformed data described (14, 18). The anti-EpCAM mAb was HT29/26 (IgG2a, ATCC; sets normalized to median chip intensity. Initial size of each predictor gene antigen defined by Cathy Hession at Biogen Idec, Cambridge, MA). A list was set to 50 genes using cross-validated genes with the class prediction chimeric V/Cmouse/human IgG1/ n variant of CBE11 was constructed and P cutoffs of 0.2. For hierarchical clustering analysis, expression values of the produced at Biogen Idec. An IgM version of the chimeric CBE11 was selected predictor genes were averaged for each group of samples repre- engineered by extending the heavy chain COOH terminus with 18 amino senting a given cell line or class of clinical tumor samples and standardized acids of human mu chain to force pentamerization as described (19). This using the mean and SD values of the resulting groups of averaged samples. pentameric antibody was purified by protein A affinity followed by size Immunohistochemistry. Formalin-fixed paraffin-embedded tissue sec- exclusion chromatography and called CBE11p. A fully humanized version of tions (Imgenex slides, San Diego, CA) were deparaffinized and blocked with CBE11 was created by humanization of the variable domains of the mouse/ 2% horse serum in PBS. Due to poor performance of CBE11 in the staining human chimeric CBE11. A chimeric
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