title: A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.
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.
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Translational Science, MedImmune, Gaithersburg, Maryland.
authors.forename: April
authors.initials: A
authors.lastname: Davis
authors.affiliation: Aileron Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Maria
authors.initials: M
authors.lastname: Ouzounova
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Carrasco
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Cui
authors.initials: C
authors.lastname: Chen
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Shannon
authors.initials: S
authors.lastname: Breen
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Yong S
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hurt
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Moisan
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia.
authors.forename: Michael
authors.initials: M
authors.lastname: Fung
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.affiliation: Translational Science, MedImmune, Gaithersburg, Maryland.
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Translational Science, MedImmune, Gaithersburg, Maryland.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: Aileron Therapeutics, Inc., Cambridge, Massachusetts. hollingsworthr@medimmune.com hkorkaya@gru.edu.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Oncology Research, MedImmune, Gaithersburg, Maryland. hollingsworthr@medimmune.com hkorkaya@gru.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015398:Signal Transduction; D000068878:Trastuzumab / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D015850:Interleukin-6; D000068878:Trastuzumab