Elevated levels of the proinflammatory
cytokine IL6 are associated with poor survival outcomes in many
cancers.
Antibodies targeting
IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit
cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on
IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several
tumor types driven by
IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for
IL6 in promoting
tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce
IL6 and support
tumorigenesis. Notably, in
tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of
chemotherapy or
gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against
trastuzumab-resistant HER2(+)
tumor cells by targeting the CD44(+)CD24(-) cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of
IL6 in
tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of
IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance.