A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors

Haihong Zhong, April Davis, Maria Ouzounova, Rosa A. Carrasco, Cui Chen, Shannon Breen, Yong S. Chang, Jiaqi Huang, Zheng Liu, Yihong Yao, Elaine Hurt, Jacques Moisan, Michael Fung, David A. Tice, Shawn G. Clouthier, Zhan Xiao, Max S. Wicha, Hasan Korkaya, Robert E. Hollingsworth

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)480-490
Number of pages11
JournalCancer Research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016
Externally publishedYes

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Interleukin-6
Drug Therapy
Antibodies
Neoplasms
Drug Resistance
Xenograft Model Antitumor Assays
Anti-Idiotypic Antibodies
Carcinogenesis
Autocrine Communication
Trastuzumab
Interleukin-6 Receptors
Neoplastic Stem Cells
Growth
Half-Life
Chronic Disease
Endothelial Cells
Cytokines
Survival
Therapeutics
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhong, H., Davis, A., Ouzounova, M., Carrasco, R. A., Chen, C., Breen, S., ... Hollingsworth, R. E. (2016). A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors. Cancer Research, 76(2), 480-490. https://doi.org/10.1158/0008-5472.CAN-15-0883

A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors. / Zhong, Haihong; Davis, April; Ouzounova, Maria; Carrasco, Rosa A.; Chen, Cui; Breen, Shannon; Chang, Yong S.; Huang, Jiaqi; Liu, Zheng; Yao, Yihong; Hurt, Elaine; Moisan, Jacques; Fung, Michael; Tice, David A.; Clouthier, Shawn G.; Xiao, Zhan; Wicha, Max S.; Korkaya, Hasan; Hollingsworth, Robert E.

In: Cancer Research, Vol. 76, No. 2, 15.01.2016, p. 480-490.

Research output: Contribution to journalArticle

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 2016, 'A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors', Cancer Research, vol. 76, no. 2, pp. 480-490. https://doi.org/10.1158/0008-5472.CAN-15-0883
Zhong, Haihong ; Davis, April ; Ouzounova, Maria ; Carrasco, Rosa A. ; Chen, Cui ; Breen, Shannon ; Chang, Yong S. ; Huang, Jiaqi ; Liu, Zheng ; Yao, Yihong ; Hurt, Elaine ; Moisan, Jacques ; Fung, Michael ; Tice, David A. ; Clouthier, Shawn G. ; Xiao, Zhan ; Wicha, Max S. ; Korkaya, Hasan ; Hollingsworth, Robert E. / A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors. In: Cancer Research. 2016 ; Vol. 76, No. 2. pp. 480-490.
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AU - Breen, Shannon

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