title: MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential.
abstract: Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD). MEDI1873 was optimized through systematic testing of different trimerization domains, aglycosylation of the GITRL ECD and comparison of different Fc isotypes. MEDI1873 exhibits oligomeric heterogeneity and superiority to an anti-GITR antibody with respect to evoking robust GITR agonism, T-cell activation and clustering of Fc gamma receptors. Further, it recapitulates,in vitro, several aspects of GITR targeting described in mice, including modulation of regulatory T-cell suppression and the ability to increase the CD8+:CD4+T-cell ratio via antibody-dependent T-cell cytotoxicity. To support translation into a therapeutic setting, we demonstrate that MEDI1873 is a potent T-cell agonistin vivoin non-human primates, inducing marked enhancement of humoral and T-cell proliferative responses against protein antigen, and demonstrate the presence of GITR- and FoxP3-expressing infiltrating lymphocytes in a range of human tumors. Overall our data provide compelling evidence that MEDI1873 is a novel, potent GITR agonist with the ability to modulate T-cell responses, and suggest that previously described GITR biology in mice may translate to the human setting, reinforcing the potential of targeting the GITR pathway as a therapeutic approach to cancer.
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Tigue
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bamber
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Ireland
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Hair
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Carter
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Sudharsan
authors.initials: S
authors.lastname: Sridharan
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Jovanović
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Rees
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Springall
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Solier
authors.affiliation: MedImmune LLC , Gaithersburg, MD, USA.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Li
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chodorge
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Perez-Martinez
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Higazi
authors.affiliation: MedImmune LLC , Gaithersburg, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.affiliation: MedImmune LLC , Gaithersburg, MD, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: MedImmune LLC , Gaithersburg, MD, USA.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Black
authors.affiliation: MedImmune LLC , Mountain View, CA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: MedImmune LLC , Mountain View, CA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwickart
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Maguire
authors.affiliation: MedImmune LLC , Gaithersburg, MD, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Cann
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Lolke
authors.initials: L
authors.lastname: de Haan
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Lesley L
authors.initials: LL
authors.lastname: Young
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Tristan
authors.initials: T
authors.lastname: Vaughan
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.affiliation: MedImmune Ltd , Cambridge, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
keywords: Agonist; GITR; GITRL; MEDI1873; T cell; hexamer; tumor