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Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1

Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

From the Institute for Drug Development, Cancer Therapy and Research Center; The University of Texas Health Science Center at San Antonio, San Antonio, TX; Fox Chase Cancer Center, Philadelphia, PA; and Human Genome Sciences, Rockville, MD

Address reprint requests to Anthony W. Tolcher MD, FRCP (C), Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach, Suite 414, San Antonio, TX 78229; e-mail: atolcher{at}idd.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor–related apoptosis-inducing ligand receptor-1 (TRAIL-R1).

Patients and Methods Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry.

Results Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (± standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (± 1.5 mL/d/kg) and 18.8 days (± 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months.

Conclusion Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Mapatumumab (HGS-ETR1, TRM-1) is a fully human immunoglobulin G₁ lambda (IgG₁ ) agonist monoclonal antibody that binds with high affinity to the extracellular domain of the human tumor necrosis factor (TNF)–related apoptosis-inducing ligand receptor-1 (TRAIL-R1, DR4) and activates the extrinsic apoptotic pathway. TRAIL-R1 is a member of the TNF superfamily that consists of 18 ligands and 28 receptors. The normal biologic role for these receptors is regulation of cell survival, apoptosis induction in virally infected or transformed malignant cells, and several functions outside the immune system.^1,2 After binding of either the ligand or agonist antibody to the extracellular domain of TRAIL-R1, a death-inducing signaling complex (DISC) that includes Fas-associating protein is formed with a death domain (FADD) and a serine protease, caspase 8 or 10. FADD acts as the recruitment scaffold for the inactive forms of caspase 8 or 10. The DISC promotes cleavage and activation of caspase 8 and 10 that initiates the downstream effector caspases 3, 6, and 7.² Once activated, this cascade of effector caspases degrades critical regulatory proteins and DNA, resulting in the characteristic morphology of programmed cell death.³ Mapatumumab, unlike native TRAIL, binds specifically to TRAIL-R1 and not to the other TRAIL receptors, including the decoy receptors.

Expression of TRAIL-R1 is frequently detected in human malignancies including colon, gastric, pancreatic, ovarian, breast, and carcinomas and non–small-cell lung cancer (NSCLC).⁴ In contrast, minimal or no TRAIL-R1 expression is found in healthy tissues.

Mapatumumab induced cleavage of caspases 8, 3, and 9, and intracellular targets Bcl-2 homology 3 Domain and polyadenosine diphosphate ribose polymerase, and induced apoptosis in a wide spectrum of human tumor cell lines in vitro. Mapatumumab-induced tumor regressions in mice bearing established TRAIL-R1–expressing human tumor xenografts including Colo205 (colon), H2122 (NSCLC), and A498 (renal) tumors.⁵ Furthermore, mapatumumab enhanced the antitumor activity of cytotoxic agents in several cell lines, including those not sensitive to mapatumumab or the chemotherapy agent when it is administered alone.⁵ Although TRAIL-R1 expression is requisite for mapatumumab antitumor activity, in preclinical models, there was no relationship between the magnitude of TRAIL-R1 expression and the level of activity. Therefore, the determinants of response to mapatumumab are more complex than receptor expression alone.

Preclinical studies were performed in rodents, cynomolgus monkeys, and chimpanzees. Mapatumumab binds to the chimpanzee TRAIL-R1 homolog, was a relevant species for toxicokinetic evaluation, and tolerated up to 40 mg/kg every 10 days for 6 months. Plasma elimination was biphasic, with a terminal half-life (t_1/2ß) of approximately 23 days and a volume of distribution at steady-state (V_ss) of 81 mL/kg.

The rationale for the clinical development of mapatumumab included the novel mechanism of action, the differential expression of the target TRAIL-R1 in common human tumors versus nontumor tissues, antitumor activity in a broad spectrum of TRAIL-R1–expressing experimental tumors at pharmacologically achievable doses, and the potential to enhance the induction of apoptosis in combination with current cytotoxic chemotherapy. The principal objectives of this phase I study were to determine the feasibility of intravenous mapatumumab administration, characterize the toxicities and the pharmacokinetics, describe preliminary evidence of anticancer activity, and evaluate the expression of TRAIL-R1 on patients' tumors.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patient Selection
Patients with advanced solid malignancies refractory to standard therapy or for whom no standard therapy existed were eligible. Eligibility also included age 18 years or older; life expectancy of at least 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; previous therapy of at least 4 weeks (6 weeks for prior mitomycin and nitrosoureas); hemoglobin of at least 10g/dL; platelet count of at least 100,000/µL; bilirubin 1.5x the upper limit of normal (ULN) or lower; AST, ALT, and alkaline phosphatase 2.5x the ULN or lower; serum creatinine 1.5 mg/dL or lower; no evidence of brain metastases; no evidence of HIV or hepatitis B/C seropositivity; and no coexisting severe medical conditions. Patients gave written informed consent according to federal and institutional guidelines before treatment.

Dosage and Drug Administration
Mapatumumab was administered IV over 30 minutes from the starting dose, increased successively in [1/2]log₁₀ increments, and then infused over 120 minutes at dose levels of 1, 3, and 10 mg/kg. Treatment courses were single doses in the absence of a disease response for the 0.01- to 0.1-mg/kg dose levels, and then every 28 days at the 0.3- to 10-mg/kg dose levels. After the safety was confirmed at the 10 mg/kg dose every 28 days, patients were enrolled for treatment with 10 mg/kg every 14 days.

The maximum tolerated dose (MTD) was defined as the highest dose at which less than 33% patients experienced treatment-related dose-limiting toxicity (DLT). If one of three or one of four patients experienced DLT, the cohort was expanded to six patients. DLT was defined as any grade 4 or higher hematologic event, grade 3 or higher nonhematologic toxicity (except grade 3 or higher nausea/vomiting not treated with optimal antiemetics), or grade 2 or higher allergic reaction related to mapatumumab. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.

Mapatumumab was supplied in 100 mg (10 mL) single-use vials by Human Genome Sciences Inc (Rockville, MD). Each vial was reconstituted with 5.0 mL of sterile water for injection to a concentration of 20 mg/mL in 10 mmol/L sodium citrate, 1.9% glycine, 0.5% sucrose, and 0.02% (w/v) polysorbate 80, pH 6.5, and further diluted with normal saline to a total volume of 250 mL.

Pretreatment and Follow-Up Studies
A complete history, physical examination, and laboratory studies including a complete blood count, international normalized ratio, partial thromboplastin time, and serum chemistry including electrolytes, blood urea nitrogen, creatinine, uric acid, glucose, alkaline phosphatase, lactate dehydrogenase, ALT, AST, total bilirubin, calcium, total protein, albumin, and amylase were performed pretreatment and weekly. Urinalysis was performed on days 1, 2, 5, and 8 of the first cycle and on days 1, 2, and 15 of subsequent cycles (weekly in the cohort receiving 10 mg/kg every 14 days). Pretreatment studies also included electrocardiography, relevant radiologic studies, and tumor markers. Response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).

In course 1, patients were observed for 6 hours after treatment, and a complete physical exam was performed at 24 hours. Laboratory assessments were also performed on days 2, 5, 8, 15, and 22 of course 1, weekly on subsequent courses, and on days 29 and 57 of the last course.

Plasma Pharmacokinetic Sampling and Assay
Blood specimens were collected before and at the end of the infusion and at 5 minutes, 8 and 24 hours, and days 3, 5, 8, and 15 of the first course. In the second course, specimens were collected just before dosing and at 5 minutes and 8 and 24 hours after the infusion. In subsequent courses, a specimen was collected just before dosing, and all patients had additional specimens on days 29 and 57 after the last dose. Blood samples were centrifuged at 1,500 x g for 10 minutes immediately after collection, and the plasma was stored frozen at –70°C until assayed.

Determination of Plasma Mapatumumab Concentrations
In brief, plasma samples were analyzed for mapatumumab by an enzyme-linked immunosorbent assay (ELISA) with TRAIL-R1:FLAG capture and horseradish peroxidase–labeled antihuman antibody detection. The signal was amplified by the addition of tetramethylbenzidine, followed by absorbance measurement at 450 nm. The lower limit of quantitation was 100 ng/mL.

Detection of Antimapatumumab Antibodies
Antimapatumumab antibodies were detected using two ELISA formats. The first assay detected binding of serum antimapatumumab antibodies to mapatumumab antigen–binding fragment, and the second assay measured binding of serum antimapatumumab antibodies to mapatumumab.

Pharmacokinetic Analyses
Individual plasma mapatumumab concentration-time profiles were analyzed using two- and three-compartment models with first-order elimination from the central compartment using WINNonlin (Scientific Consultant, Apex, NC; Enterprise 5.0.1.a; Pharsight Corp, Mountain View, CA). Weightings of 1, 1/p, 1/p^0.5, and 1/p² (where p is the predicted value for the observation) were assessed. Dose proportionality was assessed using a one-way analysis of variance (ANOVA) at the =.05 significance level, with Bonferroni's multiple comparison for post tests (GraphPad Prism, V4.02; GraphPad Software Inc, San Diego, CA).

Immunohistochemical Staining of Tumor Tissues
Archival formalin-fixed, paraffin-embedded tissue specimens from patients were evaluated for TRAIL-R1. Specimens were sectioned at 4 to 6 µm onto charged slides, deparaffinized, and hydrated, which was followed by epitope retrieval at 125°C (Pascal; Dako, Carpenteria, CA). A rabbit polyclonal antibody specific for TRAIL-R1 was applied with polyclonal serum Ig fractions at the same concentration but from antigen-naïve rabbits used as negative staining controls for target antigen. Primary antibody signals were amplified using the Envision+ visualization system (Dako), and detected by enzymatic conversion of 3'3-diaminobenzidine chromogen. Cell lines positive or negative for the TRAIL-R1 were used for controls. Membrane and cytoplasmic staining was scored according to intensity and distribution.

	RESULTS

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General
Forty-nine patients, whose pertinent demographic characteristics are displayed in Table 1, received a total of 158 courses of mapatumumab at doses ranging from 0.01 to 10 mg/kg. The total number of new patients treated and the number of courses at each dose level, as well as the overall dose escalation scheme, are depicted in Table 2. The median number of courses administered per patient was two (range, 1 to 20 courses).

Toxicity
Hepatic toxicity. The grade and distribution by dose and course are shown in Table 3. No clinically meaningful elevations in hepatic parameters were attributed to mapatumumab at doses below 10 mg/kg every 14 days. As noted, two patients in the cohort receiving 10 mg/kg every 14 days had elevated liver function tests considered probably related to mapatumumab. Although other patients in the 10-mg/kg cohorts also experienced transient elevations in transaminases, these events were generally observed in patients with elevated AST levels at baseline and may have been related to their underlying disease.

Other Nonhematologic Toxicities
Overall, adverse events were uncommon and mild (grade 2). The most frequent adverse events, regardless of relationship to mapatumumab, were fatigue (43%), nausea (41%), anorexia (33%), and diarrhea (29%). All related adverse events are summarized in Table 4; these events were predominantly grade 1 or 2, with the exception of the aforementioned four events that met the DLT criteria.

0-

0-

1/2,

Formation of Antimapatumumab Antibodies
There was no evidence of antimapatumumab antibody formation in any of the 49 patients.

Immunohistochemistry for TRAIL-R1 Expression
Assessable tumor specimens were received from 19 of the 49 patients. Of these, 13 had specific TRAIL-R1 staining in at least 10% of their tumor cells, and the remaining six were negative (Table A2, online only).

Antitumor Activity
No objective responses were noted. Two patients who had malignancies with documented progressive disease before study entry had durable stable disease that lasted for 9 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Mapatumumab represents the first in a series of TRAIL receptor–targeting therapies in early clinical development. Agonist-acting antibodies directed to external domains of transmembrane receptor proteins represent a novel therapeutic approach to activate receptors, particularly when the ligand may not be optimally delivered via systemic administration. Mapatumumab, directed to TRAIL-R1, exemplifies such an agent. The ligand for the receptor, TRAIL, is subject to rapid plasma CL and binds to other TRAIL receptors including TRAIL-R2 and the decoy receptors TRAIL-R3 and -R4. Mapatumumab was, therefore, selected for clinical development on the basis of its attractive properties of agonist monoclonal antibodies and combined with preclinical antitumor activity.⁵

A very conservative starting dose of 0.01 mg/kg was chosen for this first-in-man phase I study based on the high specificity of the antibody to human TRAIL-R1, the limited nonclinical safety data in vivo, and the theoretical toxicity concerns from published studies of some forms of recombinant human TRAIL.⁷ In the current study, mapatumumab doses were escalated 1,000-fold before any significant related hepatic toxicity was noted. The potential for hepatic toxicity led to close scrutiny of hepatic transaminases elevations.⁶ The majority of patients treated at 10 mg/kg had mild or modest (grade 1 or 2) elevations in AST and ALT, without elevations in bilirubin. These elevations generally occurred in patients with elevated AST levels at baseline, and the presence of liver metastases in most patients may have contributed, at least in part, to the elevations. Human hepatocytes express TRAIL-R1 at low levels and, therefore, a direct toxic injury secondary to mapatumumab binding to normal hepatocyte TRAIL-R1 is conceivable.^8,9 However, hepatic toxicity was uncommon and modest in severity, and mapatumumab could safely be administered repetitively without hepatic injury in most patients.

A constellation of mild or modest nonhematologic manifestations that included fever, myalgia, fatigue, and nausea were observed, but none were severe. No hypersensitivity reactions were observed, and, therefore, routine premedication with antihistamines and/or corticosteroids is unnecessary. Moreover, the absence of detectable antimapatumumab antibodies supports the absence of immunogenicity with this fully human antibody.

There was no clinically significant hematologic toxicity associated with mapatumumab. TRAIL-R1 expression has been documented on the B lymphocytes, and decrements in lymphocytes did occur in four of 11 patients at the highest dose level.¹⁰ Although subpopulations of lymphocytes were not determined to characterize the lymphocyte decreases, no infectious complications typical of abnormal lymphocyte function were observed.

The t_1/2,ß of approximately 18 days is consistent with that reported for other fully human antibodies, and can support dosing every 2 or 3 weeks. Initially, mapatumumab is largely limited to the blood compartment, with eventual distribution to extravascular space. Mapatumumab pharmacokinetics appear linear up to 10 mg/kg, although the distribution, but not the CL, of the 3 mg/kg dose differed from that at lower and higher doses. However, the small number of patients at each dose level and the absence of a consistent trend necessitate caution in the interpretation of pharmacokinetic linearity.

Mapatumumab plasma concentrations that portend activity in preclinical models were attained. At dose levels of 1 mg/kg or greater, trough plasma concentrations exceeded 1 µg/mL which represented the effective concentration for 90% of cells killed for mapatumumab in vitro. Furthermore, in studies of human tumor cell line xenografts tumor regressions were observed at doses of 2.5 to 10 mg/kg, and, at the latter dose, murine mapatumumab plasma concentrations ranged from 190 to 16 µg/mL for peak and trough values, respectively, equivalent to plasma concentrations attained at the 10-mg/kg dose in the current clinical study.

Because of the variable nature of TRAIL-R1 expression in human malignancies, the prevalence of TRAIL-R1 expression in patients entered into this study was examined. Specific staining for TRAIL-R1 was found in 68% of this unselected patient population and was heterogenous within and between tumors. Conversely, these results indicate that a substantial proportion of patients entered did not express the relevant target and this may impact clinical benefit assessment. Although no objective responses were observed with mapatumumab in this unselected phase I study, the presence of two patients with persistent stable disease beyond 8 months was encouraging. Furthermore, ongoing phase II studies indicate that mapatumumab has single-agent antitumor activity in non-Hodgkin's follicular B-cell lymphoma.¹¹

In the continuing development of mapatumumab, defining the optimal population that will attain maximal therapeutic effect remains an important objective. Although TRAIL-R1 expression is essential for antitumor activity in preclinical studies, the magnitude of expression alone does not predict responsiveness. The intrinsic and extrinsic apoptotic pathways are actually closely interrelated, and, therefore, single-agent antitumor activity may depend on a favorable pattern of pro- and antiapoptotic molecular determinants of response. Preclinical data suggest that deletions of Bax gene, overexpression of Bcl-2 protein, or caspase gene mutations may abrogate the effectiveness of TRAIL receptor–targeting therapies.^12,13 As such, the identification of other determinants of response, beyond the presence of the receptor, will need to be evaluated, and may have implications for the selection of optimal patients and chemotherapy regimens to combine with TRAIL receptor–targeting agents.

In conclusion, mapatumumab can be safely administered to patients with advanced malignancies at doses of 10 mg/kg every 14 days. To fully evaluate the activity of mapatumumab in tumors either as a single agent or in combination with currently available chemotherapies to enhance apoptotic effect, a broad spectrum of disease-directed studies should be undertaken.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Norma Lynn Fox, Human Genome Sciences; Wendy Halpern, Human Genome Sciences; Alfred Corey, Human Genome Sciences Leadership: N/A Consultant: Theresa Mays, Amgen; Roger B. Cohen, Human Genome Sciences Stock: Norma Lynn Fox, Human Genome Sciences; Wendy Halpern, Human Genome Sciences; Alfred Corey, Human Genome Sciences Honoraria: Theresa Mays, Amgen Research Funds: Roger B. Cohen, Human Genome Sciences Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Roger B. Cohen

Financial support: Norma Lynn Fox, Wendy Halpern, Alfred Corey

Administrative support: Norma Lynn Fox, Wendy Halpern, Alfred Corey

Provision of study materials or patients: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Roger B. Cohen

Collection and assembly of data: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

Data analysis and interpretation: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

Manuscript writing: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

Final approval of manuscript: Anthony W. Tolcher, Monica Mita, Neal J. Meropol, Margaret von Mehren, Amita Patnaik, Kristin Padavic, Monique Hill, Theresa Mays, Therese McCoy, Norma Lynn Fox, Wendy Halpern, Alfred Corey, Roger B. Cohen

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. (A) Mean plasma mapatumumab concentration–time profiles and (B) dose-normalized plasma mapatumumab concentration-time profiles during the first course. Error bars represent standard deviation. q, every.

	NOTES

 
Supported by Human Genome Sciences Inc.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Ashkenazi A: Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420-430, 2002[CrossRef][Medline]

2. Sheridan JP, Marsters SA, Pitti RM, et al: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818-821, 1997[Abstract/Free Full Text]

3. Thornberry NA, Lazebnik Y: Caspases: Enemies within. Science 281:1312-1316, 1998[Abstract/Free Full Text]

4. Halpern W, Lincoln C, Sharifi A, et al: Variable distribution of TRAIL Receptor 1 in primary human tumor and normal tissues. Eur J Cancer 2:69, 2004 (abstr 225)

5. Pukac L, Kanakaraj P, Humphreys R, et al: HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 92:1430-1441, 2005[CrossRef][Medline]

6. Human Genome Sciences I: Investigator's Brochure TRM-1 (TRAIL-R1 Agonist mAb, mapatumumab). Rockville, MD, Human Genome Science Inc, 2006

7. Lawrence D, Shahrokh Z, Marsters S, et al: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7:383-385, 2001[CrossRef][Medline]

8. Jo M, Kim TH, Seol DW, et al: Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6:564-567, 2000[CrossRef][Medline]

9. Ozoren N, Kim K, Burns TF, et al: The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 60:6259-6265, 2000[Abstract/Free Full Text]

10. Hasegawa H, Yamada Y, Harasawa H, et al: Restricted expression of tumor necrosis factor-related apoptosis-inducing ligand receptor 4 in human peripheral blood lymphocytes. Cell Immunol 231:1-7, 2004[CrossRef][Medline]

11. Younes A, Vose JM, Zelentz AD, et al: Results of a phase 2 trial of HGS-ETR1 (agonist human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin's lymphoma (NHL). Blood 106:146a, 2005 (abstr 489)

12. LeBlanc H, Lawrence D, Varfolomeev E, et al: Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 8:274-281, 2002[CrossRef][Medline]

13. Sun SY, Yue P, Zhou JY, et al: Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. Biochem Biophys Res Commun 280:788-797, 2001[CrossRef][Medline]

Submitted August 30, 2006; accepted December 14, 2006.

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				D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

				E. J. Benz Jr., D. G. Nathan, R. K. Amaravadi, and N. N. Danial Targeting the Cell Death-Survival Equation Clin. Cancer Res., December 15, 2007; 13(24): 7250 - 7253. [Full Text] [PDF]

				R. K. Amaravadi and C. B. Thompson The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment Clin. Cancer Res., December 15, 2007; 13(24): 7271 - 7279. [Abstract] [Full Text] [PDF]

				M. J.S. Dyer, M. MacFarlane, and G. M. Cohen Barriers to Effective TRAIL-Targeted Therapy of Malignancy J. Clin. Oncol., October 1, 2007; 25(28): 4505 - 4506. [Full Text] [PDF]

				T. F. Gajewski On the TRAIL Toward Death Receptor-Based Cancer Therapeutics J. Clin. Oncol., April 10, 2007; 25(11): 1305 - 1307. [Full Text] [PDF]

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