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Fully Human Anti-Interleukin 8 Antibody Inhibits Tumor Growth in Orthotopic Bladder Cancer Xenografts via Down-Regulation of Matrix Metalloproteases and Nuclear Factor-B¹

Departments of Cancer Biology [B. M. M., C. P. N. D., C. E. B., P. S., C. T., D. J. M., M. B-E.] and Urology [B. M. M., C. P. N. D., C. E. B., P. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Abgenix, Inc. [X. D. Y., J. M. G.], Fremont, California 94555

Purpose: We previously demonstrated that overexpression of interleukin 8 (IL-8) in human transitional cell carcinoma (TCC) resulted in increased tumorigenicity and metastasis. This increase in tumor growth and metastasis can be attributed to the up-regulation in the expression and activity of the metalloproteinases MMP-2 and MMP-9.

Experimental Design: To investigate whether targeting IL-8 with a fully human anti-IL-8 antibody (ABX-IL8) could be a potential therapeutic strategy for controlling TCC growth, we studied its effects on TCC growth in vitro and in an in vivo mouse model. Human TCC cell lines 253J B-V and UM UC3 (high IL-8 producers), 253J (low IL-8), and 253J transfected with the IL-8 gene (high producer) were used.

Results: ABX-IL8 had no effect on TCC cell proliferation in vitro. However, in the orthotopic nude mouse model, after 4 weeks of treatment (100 µg/week, i.p.), a significant decrease in tumor growth of both cell lines was observed. IL-8 blockade by ABX-IL8 significantly inhibited the expression, activity, and transcription of MMP-2 and MMP-9, resulting in decreased invasion through reconstituted basement membrane in vitro. The down-regulation of MMP-2 and MMP-9 in these cells could be explained by the modulation of nuclear factor-B expression and transcriptional activity by ABX-IL8.

Conclusions: Our data point to the potential use of ABX-IL8 as a modality to treat bladder cancer and other solid tumors, either alone or in combination with conventional chemotherapy or other antitumor agents.

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