title: Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival.
abstract: OBJECTIVE
  Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro.
  
  
  METHODS
  We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxol plus carboplatin chemotherapy delayed tumor progression, whereas combined treatment caused tumor regression and a substantially longer growth delay. To test apomab activity in a setting that may more closely mimic lung cancer pathology in patients, we developed a lung orthotopic model.
  
  
  RESULTS
  In this model, microcomputed tomography imaging showed that apomab, chemotherapy, or combination treatment significantly inhibited tumor growth compared with vehicle, whereas the combination caused greater inhibition in tumor growth relative to chemotherapy or apomab. Similarly, histologic analysis revealed that apomab, chemotherapy, or the combination significantly reduced tumor size compared with vehicle, whereas the combination induced significantly greater reduction in tumor size than did chemotherapy or apomab. Furthermore, combined treatment improved 105-day survival relative to vehicle (P = 0.0023) as well as to apomab (P = 0.0445) or chemotherapy (P = 0.0415).
  
  
  CONCLUSIONS
  These results show a positive interaction of apomab with chemotherapy, evidenced by significant inhibition of tumor growth as well as improved survival, thus supporting further investigation of this therapeutic approach in lung cancer patients.
authors.affiliation: Department of Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Jin
authors.forename: Renhui
authors.initials: R
authors.lastname: Yang
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.forename: Sharon
authors.initials: S
authors.lastname: Fong
authors.forename: Richard
authors.initials: R
authors.lastname: Carano
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.forename: Ralph
authors.initials: R
authors.lastname: Schwall
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C530969:apomab; D016190:Carboplatin; D017239:Paclitaxel