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Ann. Res. Therap. Vol. 13, Nos. 1 & 2, pp. 11-16, 2005

Current status of -related -inducing receptor (TRAIL-R) targeting cancer therapy

Eiji Mori, Kazuhiro Motoki and Shiro Kataoka

Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., Gunma, Japan

Abstract Monoclonal antibodies have already established a secure position as a very promising strategy for anti-tumor therapeu- tics. High specificity and high affinity are attractive characteristics of antibodies which make them suitable for clinical applications. Advances in genetic engineering have enabled to generate recombinant antibodies which circumvent the prob- lems of using murine antibodies in human therapy. Immunological effects, specific delivery of antibody conjugated-toxins to target cancer cells, and direct effects through receptor engagement by antibodies have been exploited as mechanisms which generate anti-tumor activity. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and can induce apoptosis in a wide variety of human cancer cell lines via its interactions with TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), but does not affect most normal human cells. From the clinical viewpoint, the use of a recombinant soluble form of TRAIL and agonistic antibodies specific for TRAIL-R1 and TRAIL-R2 as anti-tumor agents have been investigated. These promising therapeutic agents are now undergoing clinical investigations. In this review, we summarize the characteristics of recently developed anti-tumor therapeutic antibodies and discuss the current status of therapeutic approaches targeting TRAIL receptors, both by application of TRAIL and by treatment with agonistic monoclonal antibodies. Both these strategies show great promise as therapeutic agents for treatment of cancer patients.

Key words: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TRAIL receptor 1 (TRAIL-R1), TRAIL receptor 2 (TRAIL-R2), apoptosis, KM mouseTM , , targeting, therapeutics

(Received November 24, 2004; Accepted February 18, 2005)

Monoclonal antibody-based cancer genic mAbs, that is, chimeric antibodies and humanized immunotherapy antibodies. Chimeric antibodies consist of the mouse immunoglobulin (Ig) variable regions fused to human Recently, several therapeutic strategies for the treat- Ig constant regions. Humanized antibodies, which have ment of tumors have employed monoclonal antibodies only the complementarity determining region (CDR) (mAbs)1-4). Significant characteristics of mAbs such as of the murine antibody6), are much less antigenic than high specificity and high affinity toward their antigens mouse mAbs or chimeric antibodies. Additionally, new were predicted to offer advantages for cancer treatment. technologies using libraries and transgenic The advent of hybridoma technology by Köhler and mice expressing human Ig genes7-11) have enabled to gen- Milstein in the 1970s, enabled the large-scale preparation erate fully human antibodies. of mAbs against a specific antigen and the administra- The mechanism of action of therapeutic antibod- tion of exogenous antibodies for cancer therapeutics5). ies has been diligently examined. Antibody-dependent Although some early trials using murine mAbs were suc- cell-mediated cytotoxicity (ADCC) and complement- cessful, the antigenicity of the murine mAbs was prob- dependent cytotoxicity (CDC) are possible immunologi- lematic. The murine antibodies induced production of cal effects of therapeutic antibodies. The anti-tumor human anti-mouse antibodies (HAMA) in patients, and activity of Rituxan, a chimeric anti-CD20 antibody for resulted in rapid clearance of the injected murine anti- treatment of lymphomas, may be attributable to a com- bodies from the serum. In the 1980s, advances in genetic bination of mechanisms, but ADCC and CDC appear to engineering technology enabled to generate less anti- play a prominent role. In the case of Herceptin, a human- ized anti-HER2/neu antibody for , the clini- Corresponding to: Shiro Kataoka, Pharmaceutical Research Laboratories, cal activity of the antibody may be the result of several Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma, 370-1295, Japan, Tel: +81-27-346-9788, Fax : +81-27-346-1971, E-mail : [email protected], mechanisms, including ADCC.

Current status of tumor necrosis TRAIL-R target 11 In addition to the immunological effects, antibodies receptors, TRAIL-R3 (TRID/DcR1), which lacks a can be engineered to deliver a cytotoxic agent or ioniz- , TRAIL-R4 (DcR2), which contains a ing radiation to the tumor. Mylotarg is a calicheamicin- truncated non-functional death domain, and osteopro- conjugated mAb directed toward CD33. It has been re- tegerin (OPG), which is a soluble identified as ported to be relatively well tolerated and effective in the a receptor for RANKL/OPGL, have been proposed to treatment of chronic lymphocytic leukemia12). Patients act as decoy receptors, thereby limiting TRAIL avail- with relapsed or refractory low-grade non-Hodgkin’s ability. Interestingly, down-regulation of TRAIL-R3 lymphoma treated with a yttrium-90- or an iodine- and TRAIL-R4 by promoter hypermethylation has been 131-conjugated mAb to CD20 (Zevalin and Bexxar, observed in tumor cells like neuroblastomas22), and may respectively) showed a statistically significant increase render the cells more sensitive to TRAIL-induced apop- in overall response compared with those treated with an tosis. unlabeled mAb to CD20, Rituxan, in a Phase III ran- TRAIL induces apoptosis signals via TRAIL-R1 domized study13). and/or TRAIL-R2, which engage the “extrinsic” apop- Moreover, antibodies can exhibit anti-tumor effects tosis pathway23). Upon binding of TRAIL, TRAIL-R1 directly through their interactions with cell surface re- and TRAIL-R2 can recruit and activate -8 and ceptors, by blocking ligands from binding their cognate caspase-10. These two then activate the effector receptors14) or by induction of apoptosis15,16). For example, caspases, such as caspase-3, -6 and -7. In some cancer the mechanism of action of ABX-EGF17), a human mAb cell lines, caspase-3 activation induced by TRAIL is to the epidermal (EGF) receptor, is neither further amplified through the “intrinsic” apoptosis path- ADCC nor CDC. ABX-EGF binds to the EGF receptor, way via mitochondria and caspase-924-26). Therefore, the blocks binding of endogenous ligands and downstream “extrinsic” and “intrinsic” apoptosis signaling pathways signaling, and thereby elicits its anti-tumor activity communicate with, and may modulate, each other. against colorectal cancer. Agonistic anti-TRAIL-R1 and TRAIL-R2 mAbs, which are discussed in detail below, Therapeutic approaches using TRAIL can mimic the TRAIL ligand and transmit apoptosis signals via these receptors, resulting in the induction of Death receptor ligands such as TNF, FasL and TRAIL tumor cell death. have been considered useful for cancer therapeutics because they could induce apoptosis in tumor cells in- TRAIL-mediated apoptosis dependently of the tumor suppressor p53. However, several studies have found that treatment with either TNF The tumor necrosis factor (TNF)-related apoptosis-in- or anti-Fas antibodies was toxic to normal tissues27,28). ducing ligand (TRAIL) was identified from its sequence Intravenous TNF administration caused hypotension homology to members of the TNF superfamily18,19). The and a systemic inflammatory syndrome similar to septic protein sequence of TRAIL is 23% and 19% identical . Hepatocyte death and lethal hepatic failure were to (FasL) and TNF, respectively. TRAIL is a observed in mice injected with agonistic anti-Fas anti- type II transmembrane protein and its extracellular re- bodies. gion can be proteolytically cleaved to release the soluble In contrast, the soluble form of TRAIL potently in- bioactive ligand. The biological role of TRAIL is not duces apoptosis in a wide variety of human tumor cell fully understood; however, recent evidence strongly sug- lines, including those derived from breast, colon, kidney, gests that TRAIL may play an important role in immune lung, pancreas, prostate, central nervous system, and surveillance against malignant transformed and virus- thyroid , as well as leukemia, lymphoma, and infected cells. multiple myeloma29,30). But, when tested in vitro, soluble TRAIL binds five known receptors20), all of which TRAIL did not exhibit this activity toward most nor- belong to the TNF receptor (TNFR) superfamily. They mal human cell types including endothelial, epithelial, are type I transmembrane containing cysteine , and smooth muscle cells, astrocytes29,31), he- rich domain (CRD) motifs, which are defined by sev- patocytes32), and keratinocytes33). Furthermore, TRAIL eral cysteine residues in highly conserved positions in exhibits anti-tumor activity in mouse xenograft models an extracellular domain21). Two receptors, TRAIL-R1 of human cancers29) and its administration to non-human (DR4) and TRAIL-R2 (DR5), contain cytoplasmic death primates produces little toxicity in normal tissues34). domains that can mediate apoptotic signaling. The ex- Based on the results of the preclinical studies, a clinical tracellular domains of TRAIL-R1 and TRAIL-R2 are study using recombinant soluble TRAIL (PRO1762) has 58% identical, and, the intracellular death domains are been started by Genentech, Inc (South San Francisco, 65% identical. A clear difference between TRAIL-R1 CA). and TRAIL-R2 has yet to be identified; the recep- Combination therapies using TRAIL and other thera- tors appear to be functionally redundant. Three other peutics such as or radiation therapy have

12 Annals of Cancer Research and Therapy Vol. 13 Nos. 1 & 2, 2005 been keenly investigated. Synergistic interactions have that decoy receptors are a minor factor for TRAIL re- been reported between TRAIL and a number of thera- sistance in the melanoma cells used in this study. It peutic agents, including IFN-alpha35), genotoxic agents should be further examined whether the expression of such as doxorubicin, cisplatin, or etoposide36-41), irinote- decoy receptors correlates with the TRAIL sensitivity can24,29,34,42-44), gamma-radiation45,46), and cyclooxygen- in other tumor cell types. Other murine mAbs to human ase-2 inhibitors47). Although the mechanisms of these TRAIL-R1, 4H6 (mIgG1) and 4G7 (mIgG2a), developed synergies are not completely understood and are likely by Chuntharapai et al., showed a potent cytotoxic activ- to vary between therapies, the following mechanisms ity against tumor cell lines that express TRAIL-R1, upon have been suggested to influence the combination treat- cross-linking with goat anti-mouse IgG-Fc antibodies in ments synergies detected to date: receptor up-regulation, vitro; but, normal human endothelial cells, which also modulation of Bcl-2 family members, up-regulation of express TRAIL-R1, were not adversely affected55). This caspases, down-regulation of c-FLIP, which is an endog- study also indicated that rabbit and human complement enous inhibitor of “extrinsic” caspase-8 activation, and and human C1q, the first complement component, could inhibition of IAP family members, which inhibit “intrin- function as cross-linkers for the mIgG2a isotypes, but sic” caspase-3 activation. not mIgG1 isotypes. This result suggests that antibody Recombinant soluble TRAIL in a non-tagged, zinc- isotypes are critical to the cross-linking of antibodies bound trimeric form, triggered tumor cell apoptosis with endogenous cross-linkers. while sparing normal cells. However, some recombinant Cross-linking is needed to exert an agonistic activ- versions of TRAIL, which contain either an N-terminal ity of the mAbs mentioned above. As opposed to in polyhistidine tag or an N-terminal Flag epitope tag vitro conditions, in vivo cross-linkers are presumably cross-linked with an anti-Flag antibody, induced death of limited to the complement component C1q and the Fc normal cells such as hepatocytes32) and keratinocytes33). receptors on immune effector cells55,56), which may be TRAIL expression induced by adenovirus gene transfer variable among individual patients. Therefore, a direct is also effective in killing normal human hepatocytes in agonist to TRAIL receptors that can induce apoptosis vitro48). In addition, cholestasis, one of the common fea- without cross-linkers may be more effective in cancer tures of injury or dysfunction, sensitized the liver therapeutics. More recently, we succeeded in generating to TRAIL hepatotoxicity49). Although considerable con- a direct agonist mAb to TRAIL-R2 (KMTR2), which troversy surrounds the potential hepatocyte toxicity of showed potent agonistic activity both in vitro and in vivo, soluble TRAIL50,51), these observations present the pos- independent of cross-linking57). However, as previously sibility that TRAIL might trigger the apoptosis of human discussed30), agonistic activity of mAbs in the absence liver cells in vivo. of cross-linking agents may be due to the presence of antibody aggregates, as is the case with anti-Fas mAbs15) Therapeutic approaches using monoclonal and anti-CD40 mAbs58). To investigate this possibility, anti-TRAIL-R1/R2 antibodies we purified KMTR2 by size-exclusion chromatography to obtain a monomer fraction of antibody, excluding Because decoy receptors can protect cells from aggregates. In the absence of cross-linkers, highly puri- TRAIL-induced apoptosis when over-expressed52,53), fied monomers of KMTR2 exhibited apoptosis-inducing some tumor cells may circumvent TRAIL signal-induced activity, comparable to the activity seen with cross- apoptosis by up-regulating decoy receptors. Thus, spe- linking of this mAb, indicating that the agonistic activity cifically targeting TRAIL-R1 and/or TRAIL-R2 using of KMTR2 is attributable to the monomer antibody, not agonistic antibodies may be more effective in cell killing antibody aggregates. than application of TRAIL to such cells. Recently, the The activity of another murine mAb to human activity of agonistic mAbs specific to TRAIL-R1 and TRAIL-R2 (TRA-8) has been reported by Ichikawa et TRAIL-R2 has been reported. al.59). TRA-8 demonstrated apoptosis-inducing activity The first report of mAbs specific to TRAIL recep- comparable to TRAIL in TRAIL-sensitive tumor cell tors was provided by Griffith et al.54). They generated lines, but not in TRAIL-resistant normal cells in vitro, murine mAbs to human TRAIL-R1, -R2, -R3, and -R4 and elicited tumoricidal activity in mouse xenograft and revealed that the TRAIL-R1 specific and TRAIL-R2 models of human cancers. In addition, TRA-8 did not specific mAbs had the ability to induce caspase-depen- bind to normal human hepatocytes, and, therefore, it dent apoptosis in TRAIL-sensitive melanoma cells upon did not cause hepatocyte toxicity in vitro. The authors cross-linking by immobilization in vitro. Sensitivity suggest that the hepatocyte resistance to TRA-8 indi- of the melanoma cells to the anti-TRAIL-R1 mAb or cates that normal human hepatocytes express little or the anti-TRAIL-R2 mAb was comparable to the sen- no TRAIL-R2 on the cell surface. To investigate the sitivity to TRAIL, suggesting that either TRAIL-R1 contribution of each TRAIL receptor in induction of or TRAIL-R2 is sufficient to mediate cell death and tumor cell apoptosis and hepatocyte toxicity, we gener-

Current status of tumor necrosis TRAIL-R target 13 ated fully human mAbs, specific to human TRAIL-R1 ies to TRAIL-R1 and TRAIL-R2 engaged the death and TRAIL-R2, using the KM MouseTM 60). These mice receptors and induced apoptosis in a wide variety of possess the human fragment encoding the cancer cells, while having little effect on normal cells. entire human immunoglobulin heavy chain locus and the Such characteristics indicate the potential utility of the YAC-transgene containing the human immunoglobulin TRAIL-TRAIL receptor system for the treatment of hu- kappa chain gene and produce fully human anti- man cancers. At present, both ligand and antibodies are bodies when immunized61). We successfully produced undergoing clinical investigations. Their efficacy and 3 human mAbs to TRAIL-R1 and 4 human mAbs to safety will hopefully be confirmed in the near future, TRAIL-R2, and have characterized the activity of these and the targeting of TRAIL-R1 and/or TRAIL-R2 will mAbs. Upon cross-linking, all of mAbs to TRAIL-R1 be an effective treatment for a broad spectrum of tumors. and TRAIL-R2 induced apoptotic cell death in several cancer cell lines susceptible to TRAIL, but not in hu- References 1) Glennie, M.J. and Johnson, P.W. (2000). Clinical trials of antibody man umbilical vein endothelial cells, which are resistant therapy. Immunol Today 21: 403-410. to TRAIL. Three of the anti-TRAIL-R1 mAbs and two 2) Dillman, R.O. (2001). Monoclonal antibody therapy for lymphoma: of the anti-TRAIL-R2 mAbs also caused cell death in an update. Cancer Pract 9: 71-80. hepatocytes; however, two of the mAbs to TRAIL-R2 3) Countouriotis, A., Moore, T.B. and Sakamoto, K.M. (2002). Cell surface antigen and molecular targeting in the treatment of hema- showed little hepatocyte toxicity. In contrast to the re- tologic malignancies. Stem Cells 20: 215-229. sults with TRA-8, our results strongly suggest that both 4) Von Mehren, M., Adams, G.P. and Weiner, L.M. (2003). functional TRAIL-R1 and TRAIL-R2 are expressed on Monoclonal antibody therapy for cancer. Annu Rev Med 54: 343-369. normal human hepatocytes and are competent to respond 5) Köhler, G. and Milstein, C. (1975). Continuous cultures of fused to TRAIL signaling. Recently, immunohistochemical cells secreting antibody of predefined specificity. Nature 256: analyses revealed that both TRAIL-R1 and TRAIL-R2 495-497. proteins were present in human liver sections62). Again, 6) Jones, P.T., Dear, P.H., Foote, J., Neuberger, M.S. and Winter, G. (1986). Replacing the complementarity-determining regions in a these results demonstrated that some agonistic mAbs human antibody with those from a mouse. Nature 321: 522-525. to TRAIL-R2 circumvented severe hepatocyte toxicity 7) Fishwild, D.M., O’Donnell, S.L., Bengoechea, T., Hudson, D.V., though functional TRAIL-R2 was expressed on the sur- Harding, F., Bernhard, S.L., Jones, D., Kay, R.M., Higgins, K.M., Schramm, S.R. and Lonberg, N. (1996). High-avidity human IgG face of human hepatocytes. monoclonal antibodies from a novel strain of minilocus transgenic It has been reported that repeated administration of a mice. Nat Biotechnol 14: 845-851. murine agonistic mAb to mouse TRAIL-R2 caused no 8) Mendez, M.J., Green, L.L., Corvalan, J.R., Jia, X.C., Maynard- detectable systemic or organ-specific toxicity in mouse63). Currie, C.E., Yang, X.D., Gallo, M.L., Louie, D.M., Lee, D.V., Erickson, K.L., Luna, J., Roy, C.M., Abderrahim, H., TRAIL-TRAIL receptors system in murine is relatively Kirschenbaum, F., Noguchi, M., Smith, D.H., Fukushima, A., different from that in human64), suggesting that the re- Hales, J.F., Klapholz, S., Finer, M.H., Davis, C.G., Zsebo, K.M. sponse caused by the administration of the agonistic and Jakobovits, A. (1997). Functional transplant of megabase hu- man immunoglobulin loci recapitulates human antibody response antibodies to TRAIL-R2 may differ between human and in mice. Nat Genet 15: 146-156. mouse. Sciences, Inc. (Rockville, MD) 9) Tomizuka, K., Yoshida, H., Uejima, H., Kugoh, H., Sato, K., is currently conducting clinical trials of fully human Ohguma, A., Hayasaka, M., Hanaoka, K., Oshimura, M. and agonistic mAbs targeting TRAIL-R1 (HGS-ETR1) and Ishida, I. (1997). Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nat Genet TRAIL-R2 (HGS-ETR2 and HGS-TR2J). The results of 16: 133-143. these clinical studies will further elucidate the benefit of 10) Green, L.L. (1999). Antibody engineering via genetic engineering mAbs to TRAIL receptors for cancer therapeutics. of the mouse: XenoMouse strains are a vehicle for the facile gen- eration of therapeutic human monoclonal antibodies. J Immunol Methods 231: 11-23. Conclusions 11) Tomizuka, K., Shinohara, T., Yoshida, H., Uejima, H., Ohguma, A., Tanaka, S., Sato, K., Oshimura, M. and Ishida, I. (2000). Double Monoclonal antibodies already occupy an impor- trans-chromosomic mice: maintenance of two individual human chromosome fragments containing Ig heavy and kappa loci and ex- tant position in cancer therapeutics. Several antibodies pression of fully human antibodies. Proc Natl Acad Sci U S A 97: against hematological malignancies and solid tumors are 722-727. currently, or soon will be, in clinical stages. In the initial 12) Estey, E.H., Giles, F.J., Beran, M., O’Brien, S., Pierce, S.A., Faderl, S.H., Cortes, J.E. and Kantarjian, H.M. (2002). Experience with stages of clinical application of antibodies, emphasis was gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid on the immunological effects such as ADCC and CDC, in untreated acute promyelocytic leukemia. Blood 99: 4222-4224. and the antigen specificity of antibodies used for toxin 13) Witzig, T.E., Gordon, L.I., Cabanillas, F., Czuczman, M.S., delivery. Additionally, the direct effect of antibodies on Emmanouilides, C., Joyce, R., Pohlman, B.L., Bartlett, N.L., Wiseman, G.A., Padre, N., Grillo-Lopez, A.J., Multani, P. and tumors through receptor engagement has been proposed White, C.A. (2002). Randomized controlled trial of yttrium-90–la- as an important characteristic that can be used to gener- beled ibritumomab tiuxetan radioimmunotherapy versus ate highly effective immunotherapeutics. immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Recombinant soluble TRAIL and agonistic antibod-

14 Annals of Cancer Research and Therapy Vol. 13 Nos. 1 & 2, 2005 Oncol 20: 2453-2463. lated apoptosis-inducing ligand leads to selective killing of glioma 14) Yang, X.D., Jia, X.C., Corvalan, J.R., Wang, P., Davis, C.G. and cells. Clin Cancer Res 7: 1362-1369. Jakobovits, A. (1999). Eradication of established tumors by a fully 32) Lawrence, D., Shahrokh, Z., Marsters, S., Achilles, K., Shih, D., human monoclonal antibody to the epidermal growth factor recep- Mounho, B., Hillan, K., Totpal, K., DeForge, L., Schow, P., Hooley, tor without concomitant chemotherapy. Cancer Res 59: 1236-1243. J., Sherwood, S., Pai, R., Leung, S., Khan, L., Gliniak, B., Bussiere, 15) Trauth, B.C., Klas, C., Peters, A.M., Matzku, S., Moller, P., Falk, W., J., Smith, C.A., Strom, S.S., Kelley, S., Fox, J.A., Thomas, D. and Debatin, K.M. and Krammer, P.H. (1989). Monoclonal antibody- Ashkenazi, A. (2001). Differential hepatocyte toxicity of recombi- mediated tumor regression by induction of apoptosis. Science 245: nant Apo2L/TRAIL versions. Nat Med 7: 383-385. 301-305. 33) Qin, J., Chaturvedi, V., Bonish, B. and Nickoloff, B.J. (2001). 16) Ishizuka, H., Watanabe, M., Kubota, T., Matsuzaki, S.W., Otani, Y. Avoiding premature apoptosis of normal epidermal cells. Nat Med and Kitajima, M. (1998). Antitumor activity of murine monoclonal 7: 385-386. antibody NCC-ST-421 on human cancer cells by inducing apopto- 34) Kelley, S.K., Harris, L.A., Xie, D., Deforge, L., Totpal, K., sis. Anticancer Res 18: 2513-2518. Bussiere, J. and Fox, J.A. (2001). Preclinical studies to predict 17) Yang, X.D., Jia, X.C., Corvalan, J.R., Wang, P. and Davis, C.G. the disposition of Apo2L/tumor necrosis factor-related apoptosis- (2001). Development of ABX-EGF, a fully human anti-EGF re- inducing ligand in humans: characterization of in vivo efficacy, ceptor monoclonal antibody, for cancer therapy. Crit Rev Oncol pharmacokinetics, and safety. J Pharmacol Exp Ther 299: 31-38. Hematol 38: 17-23. 35) Shigeno, M., Nakao, K., Ichikawa, T., Suzuki, K., Kawakami, A., 18) Wiley, S.R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.P., Abiru, S., Miyazoe, S., Nakagawa, Y., Ishikawa, H., Hamasaki, K., Nicholl, J.K., Sutherland, G.R., Smith, T.D., Rauch, C., Smith, C.A. Nakata, K., Ishii, N. and Eguchi, K. (2003). -alpha sensi- and Goodwin, R.G. (1995). Identification and characterization of a tizes human hepatoma cells to TRAIL-induced apoptosis through new member of the TNF family that induces apoptosis. Immunity 3: DR5 upregulation and NF-kappa B inactivation. Oncogene 22: 673-682. 1653-1662. 19) Pitti, R.M., Marsters, S.A., Ruppert, S., Donahue, C.J., Moore, A. 36) Arizono, Y., Yoshikawa, H., Naganuma, H., Hamada, Y., and Ashkenazi, A. (1996). Induction of apoptosis by Apo-2 ligand, Nakajima, Y. and Tasaka, K. (2003). A mechanism of resistance to a new member of the tumor necrosis factor receptor family. J Biol TRAIL/Apo2L-induced apoptosis of newly established glioma cell Chem 271: 12687-12690. line and sensitisation to TRAIL by genotoxic agents. Br J Cancer 20) Ashkenazi, A. and Dixit, V.M. (1998). Death receptors: signling 88: 298-306. and modulation. Science 281: 1305-1308. 37) Bouralexis, S., Findlay, D.M., Atkins, G.J., Labrinidis, A., Hay, S. 21) Locksley, R.M., Killeen, N. and Lenardo, M.J. (2001). The TNF and Evdokiou, A. (2003). Progressive resistance of BTK-143 os- and TNF receptor superfamilies: integrating mammalian biology. teosarcoma cells to Apo2L/TRAIL-induced apoptosis is mediated Cell 104: 487-501. by acquisition of DcR2/TRAIL-R4 expression: resensitisation with 22) van Noesel, M.M., van Bezouw, S., Salomons, G.S., Voute, P.A., chemotherapy. Br J Cancer 89: 206-214. Pieters, R., Baylin, S.B., Herman, J.G. and Versteeg R. (2002). 38) Miao, L., Yi, P., Wang, Y. and Wu, M. (2003). Etoposide upregu- Tumor-specific down-regulation of the tumor necrosis factor- lates Bax-enhancing tumour necrosis factor-related apoptosis related apoptosis-inducing ligand decoy receptors DcR1 and DcR2 inducing ligand-mediated apoptosis in the human hepatocellular is associated with dense promoter hypermethylation. Cancer Res carcinoma cell line QGY-7703. Eur J Biochem 270: 2721-2731. 62: 2157-2161. 39) Hotta, T., Suzuki, H., Nagai, S., Yamamoto, K., Imakiire, A., 23) LeBlanc, H.N. and Ashkenazi, A. (2003). Apo2L/TRAIL and its Takada, E., Itoh, M. and Mizuguchi, J. (2003). Chemotherapeutic death and decoy receptors. Cell Death Differ 10: 66-75. agents sensitize sarcoma cell lines to tumor necrosis factor-related 24) LeBlanc, H., Lawrence, D., Varfolomeev, E., Totpal, K., Morlan, J., apoptosis-inducing ligand-induced caspase-8 activation, apoptosis Schow, P., Fong, S., Schwall, R., Sinicropi, D. and Ashkenazi, A. and loss of mitochondrial membrane potential. J Orthop Res 21: (2002). Tumor-cell resistance to death receptor–induced apoptosis 949-957. through mutational inactivation of the proapoptotic Bcl-2 homolog 40) Jones, D.T., Ganeshaguru, K., Mitchell, W.A., Foroni, L., Baker, Bax. Nat Med 8: 274-281. R.J., Prentice, H.G., Mehta, A.B. and Wickremasinghe, R.G. (2003). 25) Deng, Y., Lin, Y. and Wu, X. (2002). TRAIL-induced apoptosis Cytotoxic drugs enhance the ex vivo sensitivity of malignant cells requires Bax-dependent mitochondrial release of Smac/DIABLO. from a subset of acute myeloid leukaemia patients to apoptosis Dev 16: 33-45. induction by tumour necrosis factor receptor-related apoptosis- 26) Ravi, R. and Bedi, A. (2002). Requirement of BAX for TRAIL/ inducing ligand. Br J Haematol 121: 713-720. Apo2L-induced apoptosis of colorectal cancers:synergism with 41) Xu, Z.W., Kleeff, J., Friess, H., Buchler, M.W. and Solioz, M. Sulindac-mediated inhibition of Bcl-xL. Cancer Res 62: 1583-1587. (2003). Synergistic cytotoxic effect of TRAIL and in 27) Hersh, E.M., Metch, B.S., Muggia, F.M., Brown, T.D., Whitehead, cells. Anticancer Res 23: 251-258. R.P., Budd, G.T., Rinehart, J.J., Crawford, E.D., Bonnet, J.D. and 42) Gliniak, B. and Le, T. (1999). Tumor necrosis factor-related apop- Behrens, B.C. (1991). Phase II studies of recombinant human tumor tosis-inducing ligand’s antitumor activity in vivo is enhanced by necrosis factor alpha in patients with malignant : a sum- the chemotherapeutic agent CPT-11. Cancer Res 59: 6153-6158. mary of the Southwest Oncology Group experience. J Immunother 43) Naka, T., Sugamura, K., Hylander, B.L., Widmer, M.B., Rustum, 10: 426-431. Y.M. and Repasky, E.A. (2002). Effects of tumor necrosis factor- 28) Ogasawara, J., Watanabe-Fukunaga, R., Adachi, M., Matsuzawa, related apoptosis-inducing ligand alone and in combination with A., Kasugai, T., Kitamura, Y., Itoh, N., Suda, T. and Nagata, S. chemotherapeutic agents on patients’ colon tumors grown in SCID (1993). Lethal effect of the anti-Fas antibody in mice. Nature 364: mice. Cancer Res 62: 5800-5806. 806-809. 44) Ray, S. and Almasan, A. (2003). Apoptosis induction in prostate 29) Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters cancer cells and xenografts by combined treatment with Apo2 li- SA, Blackie C, Chang L, McMurtrey, A.E., Hebert, A., DeForge, gand/tumor necrosis factor-related apoptosis-inducing ligand and L., Koumenis, I.L., Lewis, D., Harris, L., Bussiere, J., Koeppen, CPT-11. Cancer Res 63: 4713-4723. H., Shahrokh, Z. and Schwall, R.H. (1999). Safety and antitumor 45) Chinnaiyan, A.M., Prasad, U., Shankar, S., Hamstra, D.A., activity of recombinant soluble Apo2 ligand. J Clin Invest 104: Shanaiah, M., Chenevert, T.L., Ross, B.D. and Rehemtulla, A. 155-162. (2000). Combined effect of tumor necrosis factor-related apopto- 30) Ashkenazi, A. (2002). Targeting death and decoy receptors in the sis-inducing ligand and ionizing radiation in breast cancer therapy. tumour-necrosis factor superfamily. Nat Rev Cancer 2: 420-430. Proc Natl Acad Sci USA 97: 1754-1759. 31) Pollack, I.F., Erff, M. and Ashkenazi, A. (2001). Direct stimulation 46) Ramp, U., Caliskan, E., Mahotka, C., Krieg, A., Heikaus, S., of apoptotic signaling by soluble Apo2L/tumor necrosis factor-re- Gabbert, H.E. and Gerharz, C.D. (2003). Apoptosis induction in

Current status of tumor necrosis TRAIL-R target 15 by TRAIL and gamma-radiation is impaired antibody-based therapeutics. J Immunol 171: 562-568. by deficient caspase-9 cleavage. Br J Cancer 88: 1800-1807. 57) Motoki, K., Mori, E., Matsumoto, A., Thomas, M., Tomura, T., 47) Totzke, G., Schulze-Osthoff, K. and Janicke, R.U. (2003). Humphreys, R., Albert, V., Muto, M., Yoshida, H., Aoki, M., Cyclooxygenase-2 (cox-2) inhibitors sensitize tumor cells specifi- Tamada, T., Kuroki, R., Yoshida, H., Ishida, I., Ware, C.F. and cally to death receptor-induced apoptosis independently of COX-2 Kataoka, S. (2005). Enhanced apoptosis and tumor regression in- inhibition. Oncogene 22: 8021-8030. duced by a direct agonist antibody to TRAIL-R2. Clin Cancer Res 48) Armeanu, S., Lauer, U.M., Smirnow, I., Schenk, M., Weiss, T.S., 11: 3126-3135. Gregor, M. and Bitzer, M. (2003). Adenoviral gene transfer of tu- 58) Francisco, J.A., Donaldson, K.L., Chace, D., Siegall, C.B. and mor necrosis factor-related apoptosis-inducing ligand overcomes Wahl, A.F. (2000). Agonistic properties and in vivo antitumor an impaired response of hepatoma cells but causes severe apoptosis activity of the anti-CD40 antibody SGN-14. Cancer Res 60: in primary human hepatocytes. Cancer Res 63: 2369-2372. 3225-3231. 49) Higuchi, H., Bronk, S.F., Taniai, M., Canbay, A. and Gores, G.J. 59) Ichikawa, K., Liu, W., Zhao, L., Wang, Z., Liu, D., Ohtsuka, T., (2002). Cholestasis increases tumor necrosis factor-related apop- Zhang, H., Mountz, J.D., Koopman, W.J., Kimberly, R.P. and totis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes Zhou, T. (2001). Tumoricidal activity of a novel anti-human DR5 the liver to TRAIL-mediated cytotoxicity. J Pharmacol Exp Ther monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7: 303: 461-467. 954-960. 50) Gores, G.J. and Kaufmann, S.H. (2001). Is TRAIL hepatotoxic? 60) Mori, E., Thomas, M., Motoki, K., Nakazawa, K., Tahara, T., Hepatology 34: 3-6. Tomizuka, K., Ishida, I. and Kataoka, S. (2004). Human normal 51) Yoon, J.H. and Gores, G.J. (2002). Death receptor-mediated apop- hepatocytes are susceptible to apoptosis signal mediated by both tosis and the liver. J Hepatol 37: 400-410. TRAIL-R1 and TRAIL-R2. Cell Death Differ 11: 203-207. 52) Degli-Esposti, M.A., Dougall, W.C., Smolak, P.J., Waugh, J.Y., 61) Ishida, I., Tomizuka, K., Yoshida, H., Tahara, T., Takahashi, N., Smith. C,A. and Goodwin, R.G. (1997). The novel receptor Ohguma, A., Tanaka, S., Umehashi, M., Maeda, H., Nozaki, C., TRAIL-R4 induces NF-kappaB and protects against TRAIL- Halk, E. and Lonberg, N. (2002). Production of human monoclonal mediated apoptosis, yet retains an incomplete death domain. and polyclonal antibodies in TransChromo (TC) animals. Cloning Immunity 7: 813-820. Stem Cells 4: 91-102. 53) Degli-Esposti, M.A., Smolak, P.J., Walczak, H., Waugh, J., Huang, 62) Spierings, D.C., de Vries, E.G., Vellenga, E., van den Heuvel, F.A., C.P., DuBose, R.F., Goodwin. R.G. and Smith, C.A. (1997). Koornstra, J.J., Wesseling, J., Hollema, H. and de Jong, S. (2004). Cloning and characterization of TRAIL-R3, a novel member of the Tissue distribution of the death ligand TRAIL and its receptors. J emerging TRAIL receptor family. J Exp Med 186: 1165-1170. Histochem Cytochem 52: 821-831. 54) Griffith, T.S., Rauch, C.T., Smolak, P.J., Waugh, J.Y., Boiani, N., 63) Takeda, K., Yamaguchi, N., Akiba, H., Kojima, Y., Hayakawa, Y., Lynch, D.H., Smith, C.A., Goodwin, R.G. and Kubin, M.Z. (1999). Tanner, J.E., Sayers, T.J., Seki, N., Okumura, K., Yagita, H. and Functional analysis of TRAIL receptors using monoclonal antibod- Smyth, M.J. (2004). Induction of tumor-specific immunity ies. J Immunol 162: 2597-2605. by anti-DR5 antibody therapy. J Exp Med 199: 437-448. 55) Chuntharapai, A., Dodge, K., Grimmer, K., Schroeder, K., 64) Schneider, P., Olson, D., Tardivel, A., Browning, B., Lugovskoy, Marsters, S.A., Koeppen, H., Ashkenazi, A. and Kim, K.J. (2001). A., Gong, D., Dobles, M., Hertig, S., Hofmann, K., Van Vlijmen, Isotype-dependent inhibition of tumor growth in vivo by monoclo- H., Hsu, Y.M., Burkly, L.C., Tschopp, J. and Zheng, T.S. (2003). nal antibodies to death receptor 4. J Immunol 166: 4891-4898. Identification of a new murine tumor necrosis factor receptor locus 56) Xu, Y., Szalai, A.J., Zhou, T., Zinn, K.R., Chaudhuri, T.R., Li, X., that contains two novel murine receptors for tumor necrosis factor- Koopman, W.J. and Kimberly, R.P. (2003). Fc gamma Rs modu- related apoptosis-inducing ligand (TRAIL). J Biol Chem 278 late cytotoxicity of anti-Fas antibodies: implications for agonistic :5444-5454.

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