Reference Detail

Ref Type

Journal Article

PMID

(26744529)

Authors

Zhong H, Davis A, Ouzounova M, Carrasco RA, Chen C, Breen S, Chang YS, Huang J, Liu Z, Yao Y, Hurt E, Moisan J, Fung M, Tice DA, Clouthier SG, Xiao Z, Wicha MS, Korkaya H, Hollingsworth RE

Title

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	2	2016 Jan 15	480-90	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
MEDI5117	MEDI5117	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MEDI5117		MEDI-5117		MEDI5117 is an anti-IL6 monoclonal antibody, which inhibits IL6 autocrine signaling, potentially leading to decreased tumor cell growth (PMID: 26744529, PMID: 27237319).
Siltuximab	Sylvant	CNTO 328\|CNTO328		Sylvant (siltuxmab) is an anti-IL-6 chimeric monoclonal antibody, which inhibits IL6 signaling and may lead to decreased tumor cell growth (PMID: 26170629, PMID: 26744529). Sylvant (siltuximab) is FDA approved for patients with multicentric Castleman's disease who do not have HIV or HHV-8 (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References