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Combined Administration of Antibodies to Human Interleukin 8 and Epidermal Growth Factor Receptor Results in Increased Antimetastatic Effects on Human Breast Carcinoma Xenografts¹

Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Frederick Cancer Research and Development Center [R. S., B. G., J. J. O.]; and Intramural Research Support Program, Science Applications International Corporation, National Cancer Institute Frederick, Frederick, Maryland 21702; Department of Biology, University of California, Riverside, California 92521 [M. M-G.]

Purpose: Current antibody-based immunotherapeutic approachesunder evaluation for breast carcinoma are limited in target scope. For example, administration of the human epidermal growth factor receptor (EGFR) antibody, alone or in combination with a chemotherapeutic drug, is thought to primarily inhibit tumor cell proliferation. The aim of this study was to assess the effects of a combined blockade designed to inhibit tumor growth by inhibition of proliferation rate and the proinflammatory effects of interleukin (IL) 8.

Experimental Design: A human breast carcinoma cell line that produces high levels of IL-8 was injected s.c. into severe combined immunodeficient mice. IL-8 has been reported to augment the progression of some human tumors; thus, we used a human IL-8 antibody, ABXIL8, in combination with anti-EGFR, ABXEGFR, to inhibit the metastasis of MDA231 tumors.

Results: Whereas anti-IL-8 alone had no appreciable antimetastatic effect, the combination of ABXIL8 significantly enhanced the antitumor effects of ABXEGFR, resulting in greater survival of SCID tumor-bearing mice. This effect on survival was correlated with decreased metastatic spread and decreased tumor size in mice receiving both antibodies. Intriguingly, in vitro studies indicate that this antibody combination markedly inhibited matrix metalloproteinase activity associated with MDA-231 cells to a greater degree than either antibody alone.

Conclusion: Combined administration of these two human antibodies using growth factor blockade in conjunction with chemokine blockade may thus provide a more effective approach for treatment of metastatic human breast carcinoma.

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