HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

Abstract

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

“…A previous report showed that TRAIL-resistant THP-1 cells become sensitized to TRAIL-induced apoptosis when treated in combination with a phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor, perifosine [13]. Thus the cell-surface expression levels of DR4 and DR5 in leukemia cells are not strictly correlated with susceptibility to AY4-and TRAIL-induced cell death, in agreement with previous reports [11,28,36].…”

p53-Mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells

“…These findings might be particularly relevant to ongoing clinical trials aiming at evaluating the anti-tumoural properties of TRAIL combined with chemotherapy. Alternatively, patients exhibiting wild-type p53 tumours could benefit from ongoing phases I-II clinical trials using either agonistic anti-DR4 or anti-DR5 Oxaliplatin/TRAIL combination in colon cancer F Toscano et al antibodies in human colon cancers (Motoki et al, 2005;Pukac et al, 2005;Mita et al, 2006). We have demonstrated recently that an agonistic antibody targeting DR5 in vitro could trigger apoptosis in cells expressing the corresponding agonistic receptor even when cells harbour either of the antagonistic receptors, DcR1 or DcR2, at their cell surface (Merino et al, 2006).…”

Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway

“…Recombinant protein (such as Apo2L/TRAIL 1 ) or recombinant human agonistic anti-DR4 or anti-DR5 monoclonal antibodies 2 are commonly used to activate TRAIL receptor for the induction of apoptosis of cancer cells. Binding of trimerized TRAIL to its functional receptors DR4 and/or DR5 results in receptor aggregation, recruitment of Fass-associated death domain, procaspases 8 (and 10) and other adaptor molecules to form the death-inducing signaling complex leading to activation of these initiator caspases.…”