TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-a fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-a (tmTNF-a) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-a and its N-terminal truncated fragment on the membrane after tmTNF-a processing but does not cross-react with soluble TNF-a. We documented high levels of tmTNF-a expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-a is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-a mAb triggered antibodydependent cell-mediated cytotoxicity against tmTNF-a-expressing cells but not to tmTNF-a-negative cells. In tumor-bearing mice, tmTNF-a mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-a mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF-a-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-kB activation and Bcl-2 expression by decreasing tmTNF-a-positive cells. Overall, our results established that tmTNF-a mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-a-positive tumors, particularly in patients that are nonresponders to TNF antagonists. Cancer Res; 73(13); 4061-74. Ó2013 AACR.
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