HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo.
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-small-cell 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(-1). Clearance was 3.6-5.7 ml(-1) day(-1) kg(-1). 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.
Pukac
L
L
Human Genome Sciences Inc., 9800 Medical Center Drive, Rockville, MD 20850, USA. Laurie_Pukac@hgsi.com
Kanakaraj
P
P
Humphreys
R
R
Alderson
R
R
Bloom
M
M
Sung
C
C
Riccobene
T
T
Johnson
R
R
Fiscella
M
M
Mahoney
A
A
Carrell
J
J
Boyd
E
E
Yao
X T
XT
Zhang
L
L
Zhong
L
L
von Kerczek
A
A
Shepard
L
L
Vaughan
T
T
Edwards
B
B
Dobson
C
C
Salcedo
T
T
Albert
V
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human