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Annals of Oncology Advance Access published online on February 27, 2008
Annals of Oncology, doi:10.1093/annonc/mdn015
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

A novel humanized anti-human death receptor 5 antibody CS-1008 induces apoptosis in tumor cells without toxicity in hepatocytes

A. Yada1, M. Yazawa2, S. Ishida1, H. Yoshida2, K. Ichikawa2, S. Kurakata3 and K. Fujiwara1,*

1 Biological Research Laboratories IV
2 Advanced Technology Research Laboratories
3 Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Tokyo, Japan

* Correspondence to: Dr K. Fujiwara, Biological Research Laboratories IV, DaiichiSankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. Tel: +81-3-5696-3915; Fax: +81-3-5696-4264; E-mail: fujiwara.kosaku.t2{at}daiichisankyo.co.jp

Background: The antitumor activity of CS-1008, a humanized agonistic anti-human death receptor (DR) 5 antibody, was investigated in preclinical models.

Materials and methods: Cytotoxicity of CS-1008 was evaluated in a several human tumor cell lines as well as primary human hepatocytes in vitro. To evaluate antitumor efficacy, athymic nude mice were inoculated with human colorectal tumor COLO 205, pancreatic tumor MIA PaCa-2 or non-small-cell lung carcinoma NCI-H2122 and CS-1008 was i.v. administered. The combination effects of CS-1008 with gemcitabine or docetaxel (Taxotere) against MIA PaCa-2 or NCI-H2122 were evaluated in vivo, respectively.

Results: CS-1008 inhibited the growth of tumor cell lines with DR5 expression, including COLO 205, NCI-H2122, MIA PaCa-2 and renal cell adenocarcinoma ACHN in vitro with antibody cross-linkage. Using COLO 205, apoptosis induction was confirmed by annexin V staining. Weekly administration of CS-1008 resulted in the inhibition of COLO 205 tumor growth as well as MIA PaCa-2 in vivo. CS-1008 in combination with gemcitabine or docetaxel demonstrated enhanced antitumor activity against MIA PaCa-2 or NCI-H2122 cells, respectively. Unlike tumor necrosis factor-related apoptosis-inducing ligand, CS-1008 did not induce cell death in human primary hepatocytes.

Conclusion: CS-1008 has a selective toxicity toward tumor cells expressing DR5 and the potential for antitumor efficacy in human malignancies.

apoptosis, combination therapy, death receptor 5, humanized antibody

Received for publication December 25, 2007. Accepted for publication January 4, 2008.


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