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PloS One 2012Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of...
Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Dacarbazine; Drug Synergism; Female; Humans; Inhibitor of Apoptosis Proteins; Melanoma; Mice; Proto-Oncogene Proteins c-bcl-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays
PubMed: 23029050
DOI: 10.1371/journal.pone.0045492 -
Radiation Oncology (London, England) Oct 2009The combination of ionizing radiation with the pro-apoptotic TRAIL receptor antibody lexatumumab has been shown to exert considerable synergistic apoptotic effects in...
PURPOSE
The combination of ionizing radiation with the pro-apoptotic TRAIL receptor antibody lexatumumab has been shown to exert considerable synergistic apoptotic effects in vitro and in short term growth delay assays. To clarify the relevance of these effects on local tumour control long-term experiments using a colorectal xenograft model were conducted.
MATERIALS AND METHODS
Colo205-xenograft bearing NMRI (nu/nu) nude mice were treated with fractionated irradiation (5x 3 Gy, d1-5) and lexatumumab (0.75 mg/kg, d1, 4 and 8). The tumour bearing hind limbs were irradiated with graded single top up doses at d8 under normoxic (ambient) and acute hypoxic (clamped) conditions. Experimental animals were observed for 270 days. Growth delay and local tumour control were end points of the study. Statistical analysis of the experiments included evaluation of tumour regrowth and local tumour control.
RESULTS
Combined treatment with irradiation and lexatumumab led to a pronounced tumour regrowth-delay when compared to irradiation alone. The here presented long-term experiments revealed a highly significant rise of local tumour control for normoxic (ambient) (p = 0. 000006) and hypoxic treatment (p = 0. 000030).
CONCLUSION
Our data show that a combination of the pro-apoptotic antibody lexatumumab with irradiation reduces tumour regrowth and leads to a highly increased local tumour control in a nude mouse model. This substantial effect was observed under ambient and more pronounced under hypoxic conditions.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Hypoxia; Combined Modality Therapy; Dose-Response Relationship, Radiation; Humans; Mice; Mice, Nude; Neoplasms, Experimental; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays
PubMed: 19860913
DOI: 10.1186/1748-717X-4-49 -
Molecular Cancer Oct 2007The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe...
BACKGROUND
The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.
RESULTS
We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine.
CONCLUSION
Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cisplatin; Drug Synergism; Flow Cytometry; Humans; Immunoblotting; Jurkat Cells; Mesothelioma; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor
PubMed: 17953743
DOI: 10.1186/1476-4598-6-66 -
Tumour Biology : the Journal of the... May 2017Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our...
Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our previous article reported that small molecule YM155 induced apoptosis in pancreatic cancer cells via activation of death receptor 5. In this study, we aim to continuously address death receptor 5-mediated apoptosis in chemo-resistant pancreatic carcinoma. We found that in comparison to paired pancreatic cancer tissues and adjacent normal tissues, five of the six cancer tissues had downregulated death receptor 5 and upregulated Bcl-xL. Mono treatment with lexatumumab was not sufficient to induce apoptosis in pancreatic cancer cells, whereas focal adhesion kinase inhibitor PF573228 significantly sensitized lexatumumab-induced apoptosis. Western blotting analysis revealed that lexatumumab and PF573228 combination treatment increased death receptor 5 but decreased Bcl-xL expression. Interestingly, pre-treatment with Bcl-xL inhibitor ABT263 reversed the insensitivity of panc-1 cells to lexatumumab or PF573228-induced apoptosis. Specific small interfering RNA-mediated gene silencing of Bcl-xL effectively sensitized pancreatic cancer cells to lexatumumab or PF573228-induced apoptosis. Furthermore, lexatumumab and PF573228 combination was shown to exhibit significant xenograft pancreatic tumor growth inhibition in SCID mice. Our data provide fundamental evidence to support the notion that lexatumumab and PF573228 co-treatment could be a potentially effective regime for patients with pancreatic cancer.
Topics: Aniline Compounds; Animals; Antibodies, Monoclonal; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression Regulation, Neoplastic; Humans; Mice; Pancreatic Neoplasms; Quinolones; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sulfonamides; Sulfones; Xenograft Model Antitumor Assays; bcl-X Protein
PubMed: 28459212
DOI: 10.1177/1010428317699120 -
Journal of Clinical Oncology : Official... Nov 2012Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of...
PURPOSE
Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors.
PATIENTS AND METHODS
This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors.
RESULTS
Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response.
CONCLUSION
Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.
Topics: Adolescent; Adult; Antibodies, Monoclonal; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunohistochemistry; Male; Neoplasms; Treatment Outcome; Young Adult
PubMed: 23071222
DOI: 10.1200/JCO.2012.44.1055 -
Annals of Oncology : Official Journal... Feb 2010Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis...
BACKGROUND
Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity.
MATERIALS AND METHODS
This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.
RESULTS
Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.
CONCLUSIONS
Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.
Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 19633048
DOI: 10.1093/annonc/mdp292