title: Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death.
abstract: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL-R1, TRAIL-R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti-TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) this study demonstrated that both monoclonal antibodies activated caspase-8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one-thirds of the samples. HGS-ETR1 and HGS-ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase-8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS-ETR1 and HGS-ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.
authors.affiliation: Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center (MDACC), Houston, TX 77030, USA.
authors.forename: Georgios V
authors.initials: GV
authors.lastname: Georgakis
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Robin
authors.initials: R
authors.lastname: Humphreys
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Mamoun
authors.initials: M
authors.lastname: Younes
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Vivian
authors.initials: V
authors.lastname: Albert
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology*; D011719:Pyrazines / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists*; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D000069286:Bortezomib; D004317:Doxorubicin