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 agonist in vivo in 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.

KEYWORDS:

• Agonist
• GITR
• GITRL
• hexamer
• MEDI1873
• T cell
• tumor

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors would like to thank the following: Janette Dillon and Catherine Huntington for cell line generation, the Biologics Expression team for small scale protein expression and purification, the Early Expression Supply and Purification Process Sciences teams for large-scale expression and purification, respectively, and the DNA Chemistry and Core Tissue Culture teams. The authors would also like to acknowledge Caprion Biosciences Inc. (Québec, Canada) for support in the generation of TIL-based flow cytometry data.

Confidentiality statement

All authors are current or former salaried employees of MedImmune Ltd or MedImmune LLC (a member of the AstraZeneca Group) and have/had stock or stock options in AstraZeneca, the parent company of MedImmune.