Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity

Nature Medicine volume 7, pages 954–960 (2001)Cite this article

Abstract

A novel anti-human DR5 monoclonal antibody, TRA-8, induces apoptosis of most tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive tumor cells both in vitro and in vivo. In contrast to both the membrane-bound form of human TRAIL, which induced severe hepatitis in mice, and the soluble form of human TRAIL, which induced apoptosis of normal human hepatocytes in vitro, TRA-8 did not induce significant cell death of normal human hepatocytes. However, both primary hepatocellular carcinoma cells and an established liver cancer cell line were highly susceptible to the killing mediated by TRA-8. We show here that elevated levels of cell-surface expression of DR5 and increased susceptibility to DR5-mediated apoptosis are characteristics of malignant tumor cells. In contrast, DR5 alone is not sufficient to trigger apoptosis of normal hepatocytes. Therefore, selective, specific targeting of DR5 with an agonistic antibody might be a safe and effective strategy for cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Characterization of TRA-8.
Figure 2: Cell-surface expression of DR5 and susceptibility to DR5-mediated apoptosis.
Figure 3: Expression of DR5 in normal and cancer tissues.
Figure 4: Tumoricidal activity of TRA-8.
Figure 5: TRAIL induces hepatitis.
Figure 6: TRAIL, but not TRA-8 induces hepatocellular toxicity.

Similar content being viewed by others

References

  1. Wiley, S.R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  Google Scholar 

  2. Sheridan, J.P. et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818–821 (1997).

    Article  CAS  Google Scholar 

  3. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis- inducing ligand in vivo. Nature Med 5, 157–163 (1999).

    Article  CAS  Google Scholar 

  4. Ashkenazi, A. et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999).

    Article  CAS  Google Scholar 

  5. Pan, G. et al. The receptor for the cytotoxic ligand TRAIL. Science 276, 111–113 (1997).

    Article  CAS  Google Scholar 

  6. Walczak, H. et al. TRAIL-R2: A novel apoptosis-mediating receptor for TRAIL. EMBO J. 16, 5386–5397 (1997).

    Article  CAS  Google Scholar 

  7. Chaudhary, P.M. et al. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-κB pathway. Immunity 7, 821–830 (1997).

    Article  CAS  Google Scholar 

  8. Schneider, P. et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB. Immunity 7, 831–836 (1997).

    Article  CAS  Google Scholar 

  9. Pan, G. et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277, 815–818 (1997).

    Article  CAS  Google Scholar 

  10. Degli-Esposti, M.A. et al. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J. Exp. Med. 186, 1165–1170 (1997).

    Article  CAS  Google Scholar 

  11. Degli-Esposti, M.A. et al. The novel receptor TRAIL-R4 induces NF-κB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7, 813–820 (1997).

    Article  CAS  Google Scholar 

  12. Emery, J.G. et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J. Biol. Chem. 273, 14363–14367 (1998).

    Article  CAS  Google Scholar 

  13. Wajant, H. et al. Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2- mediated cell death but not gene induction. Curr. Biol. 8, 113–116 (1998).

    Article  CAS  Google Scholar 

  14. Yamada, H., Tada-Oikawa, S., Uchida, A. & Kawanishi, S. TRAIL causes cleavage of bid by caspase-8 and loss of mitochondrial membrane potential resulting in apoptosis in BJAB cells. Biochem. Biophys. Res. Commun. 265, 130–133 (1999).

    Article  CAS  Google Scholar 

  15. Bodmer, J.L. et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nature Cell Biol. 2, 241–243 (2000).

    Article  CAS  Google Scholar 

  16. Kuang, A.A., Diehl, G.E., Zhang, J. & Winoto, A. FADD is required for DR4- and DR5-mediated apoptosis: Lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J. Biol. Chem. 275, 25065–25068 (2000).

    Article  CAS  Google Scholar 

  17. Sprick, M.R. et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12, 599–609 (2000).

    Article  CAS  Google Scholar 

  18. Kischkel, F.C. et al. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12, 611–620 (2000).

    Article  CAS  Google Scholar 

  19. Muhlenbeck, F. et al. TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase-dependent and caspase-independent pathways. J. Biol. Chem. 273, 33091–33098 (1998).

    Article  CAS  Google Scholar 

  20. Jeremias, I. & Debatin, K.M. TRAIL induces apoptosis and activation of NFκB. Eur. Cytokine Netw. 9, 687–688 (1998).

    CAS  PubMed  Google Scholar 

  21. Herr, I. et al. JNK/SAPK activity contributes to TRAIL-induced apoptosis. Cell Death Differ. 6, 130–135 (1999).

    Article  CAS  Google Scholar 

  22. Chinnaiyan, A.M. et al. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc. Natl. Acad. Sci. USA 97, 1754–1759 (2000).

    Article  CAS  Google Scholar 

  23. Jo, M. et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor- related apoptosis-inducing ligand. Nature Med. 6, 564–567 (2000).

    Article  CAS  Google Scholar 

  24. Griffith, T.S. et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J. Immunol. 162, 2597–2605 (1999).

    CAS  PubMed  Google Scholar 

  25. Kagawa, S. et al. Antitumor activity and bystander effects of the tumor necrosis factor- related apoptosis-inducing ligand (TRAIL) gene. Cancer Res. 61, 3330–3338 (2001).

    CAS  PubMed  Google Scholar 

  26. Lawrence, D. et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nature Med 7, 383–385 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Hunter for editing the manuscript; Y. Gillespie and R. Jope for providing tumor cells; the FACS Core Facility of the University of Alabama Arthritis and Musculoskeletal Center for excellent flow cytometry assistance; the Tissue Procurement Center of the University of Alabama for providing human tissues. This work was sponsored in part by Sankyo Co. of Japan. T.Z. is supported by grants from the Juvenile Diabetes Foundation, the Arthritis Foundation, the Cystic Fibrosis Foundation and NIH R03-AR44982.

Author information

Author notes

  1. Kimihisa Ichikawa and Weimin Liu: K.I. and W.L. contributed equally to the study.

Authors and Affiliations

  1. Biomedical Research Laboratories, Sankyo Co., Tokyo, Japan

    Kimihisa Ichikawa & Toshiaki Ohtsuka

  2. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Weimin Liu, Limin Zhao, Zheng Wang, Di Liu, Huangge Zhang, John D. Mountz, William J. Koopman, Robert P. Kimberly & Tong Zhou

Authors
  1. Kimihisa Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weimin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Limin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Di Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiaki Ohtsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huangge Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John D. Mountz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William J. Koopman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert P. Kimberly
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Robert P. Kimberly or Tong Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ichikawa, K., Liu, W., Zhao, L. et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7, 954–960 (2001). https://doi.org/10.1038/91000

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/91000

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing