Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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).

CONCLUSION:

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: Hongkui Jin, Renhui Yang, Jed Ross, Sharon Fong, Richard Carano, Klara Totpal, David Lawrence, Zhong Zheng, Hartmut Koeppen, Howard Stern, Ralph Schwall, Avi Ashkenazi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 23 Pg. 7733-40 (Dec 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19047100 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• apomab
• Carboplatin
• Paclitaxel

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Immunoblotting
• In Situ Nick-End Labeling
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Nude
• Paclitaxel (administration & dosage)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, drug effects)
• Xenograft Model Antitumor Assays