A Novel Murine GITR Ligand Fusion Protein Induces Antitumor Activity as a Monotherapy That Is Further Enhanced in Combination with an OX40 Agonist.

Autor: Leyland R; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Watkins A; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Mulgrew KA; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Holoweckyj N; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Bamber L; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Tigue NJ; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Offer E; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Andrews J; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Yan L; MedImmune LLC, Mountain View, California., Mullins S; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Oberst MD; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Coates Ulrichsen J; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Leinster DA; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., McGlinchey K; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Young L; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Morrow M; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Hammond SA; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Mallinder P; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Herath A; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Leow CC; MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland., Wilkinson RW; MedImmune Ltd., Granta Park, Cambridge, United Kingdom. wilkinsonr@medimmune.com., Stewart R; MedImmune Ltd., Granta Park, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Jul 01; Vol. 23 (13), pp. 3416-3427. Date of Electronic Publication: 2017 Jan 09.
DOI: 10.1158/1078-0432.CCR-16-2000
Abstrakt: 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 EC 50 value of the mGITRL-FP was compared with an anti-GITR antibody in an in vitro agonistic 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 EC 50 value 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 .
(©2017 American Association for Cancer Research.)
Databáze: MEDLINE
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