title: A Novel Murine GITR Ligand Fusion Protein Induces Antitumor Activity as a Monotherapy That Is Further Enhanced in Combination with an OX40 Agonist.
abstract: Purpose:To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy.Experimental Design:The EC50value of the mGITRL-FP was compared with an anti-GITR antibody in anin vitroagonistic cell-based reporter assay. We assessed the impact of dose, schedule, and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared with an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models. Combination of the mGITRL-FP with antibodies targeting PD-L1, PD-1, or CTLA-4 was analyzed in mice bearing CT26 tumors.Results:The mGITRL-FP had an almost 50-fold higher EC50value compared with an anti-murine GITR antibody. Treatment of CT26 tumor-bearing mice with mGITRL-FP-mediated significant antitumor activity that was dependent on isotype, dose, and duration of exposure. The antitumor activity could be correlated with the increased proliferation of peripheral CD8+and CD4+T cells and a significant decrease in the frequency of intratumoral Tregs. The combination of mGITRL-FP with mOX40L-FP or checkpoint inhibitor antagonists enhanced antitumor immunity above that of monotherapy treatment.Conclusions:These results suggest that therapeutically targeting GITR represents a unique approach to cancer immunotherapy and suggests that a multimeric fusion protein may provide increased agonistic potential versus an antibody. In addition, these data provide, for the first time, early proof of concept for the potential combination of GITR targeting agents with OX40 agonists and PD-L1 antagonists.Clin Cancer Res; 23(13); 3416-27. ©2017 AACR.
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Leyland
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Watkins
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Mulgrew
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Holoweckyj
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bamber
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Tigue
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Offer
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Andrews
authors.affiliation: MedImmune LLC, Mountain View, California.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mullins
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Oberst
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Coates Ulrichsen
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Leinster
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Kelly
authors.initials: K
authors.lastname: McGlinchey
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Lesley
authors.initials: L
authors.lastname: Young
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morrow
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hammond
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Mallinder
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Athula
authors.initials: A
authors.lastname: Herath
authors.affiliation: MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland.
authors.forename: Ching Ching
authors.initials: CC
authors.lastname: Leow
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom. wilkinsonr@medimmune.com.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.affiliation: MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D004195:Disease Models, Animal; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology; D051379:Mice; D053278:OX40 Ligand; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D015514:Oncogene Proteins, Fusion; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors