title: A novel humanized anti-human death receptor 5 antibody CS-1008 induces apoptosis in tumor cells without toxicity in hepatocytes.
abstract: BACKGROUND
  The antitumor activity of CS-1008, a humanized agonistic anti-human death receptor (DR) 5 antibody, was investigated in preclinical models.
  
  
  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.
  
  
  CONCLUSIONS
  CS-1008 has a selective toxicity toward tumor cells expressing DR5 and the potential for antitumor efficacy in human malignancies.
authors.affiliation: Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yada
authors.forename: M
authors.initials: M
authors.lastname: Yazawa
authors.forename: S
authors.initials: S
authors.lastname: Ishida
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Ichikawa
authors.forename: S
authors.initials: S
authors.lastname: Kurakata
authors.forename: K
authors.initials: K
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D005260:Female; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000093542:Gemcitabine