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

Georgios V. Georgakis, Yang Li, Robin Humphreys, Michael Andreeff, Susan O'Brien, Mamoun Younes, Antonino Carbone, Vivian Albert, Anas Younes

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)501-510
Number of pages10
JournalBritish Journal of Haematology
Volume130
Issue number4
DOIs
Publication statusPublished - Aug 2005

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TNF-Related Apoptosis-Inducing Ligand Receptors
Death Domain Receptors
Doxorubicin
Cultured Cells
Lymphoma
Cell Death
Apoptosis
Antibodies
Caspase 8
Monoclonal Antibodies
Neoplasms
Hematologic Neoplasms
Therapeutics
Tumor Necrosis Factor-alpha
Bortezomib
Ligands
Cell Line
Proteins

Keywords

  • Apoptosis
  • Bortezomib
  • Hodgkin lymphoma
  • Leukaemia

ASJC Scopus subject areas

  • Hematology

Cite this

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. / Georgakis, Georgios V.; Li, Yang; Humphreys, Robin; Andreeff, Michael; O'Brien, Susan; Younes, Mamoun; Carbone, Antonino; Albert, Vivian; Younes, Anas.

In: British Journal of Haematology, Vol. 130, No. 4, 08.2005, p. 501-510.

Research output: Contribution to journalArticle

Georgakis, Georgios V. ; Li, Yang ; Humphreys, Robin ; Andreeff, Michael ; O'Brien, Susan ; Younes, Mamoun ; Carbone, Antonino ; Albert, Vivian ; Younes, Anas. / 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. In: British Journal of Haematology. 2005 ; Vol. 130, No. 4. pp. 501-510.
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AU - Georgakis, Georgios V.

AU - Li, Yang

AU - Humphreys, Robin

AU - Andreeff, Michael

AU - O'Brien, Susan

AU - Younes, Mamoun

AU - Carbone, Antonino

AU - Albert, Vivian

AU - Younes, Anas

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AB - 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.

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