817 DT095895, a selective EP4 receptor antagonist with monotherapy efficacy in syngeneic mouse model(s) and best-in-class properties

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A865-A865
Author(s):  
Anne-Laure Blayo ◽  
Laurène Deshons ◽  
Alexia Dumont ◽  
Christel Franchet ◽  
Célia Halter ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Receptor Antagonist ◽  
Whole Blood ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Ep4 Receptor ◽  
Ep4 Receptor Antagonist ◽  
Cox 2 ◽  
Mouse Tumor Models

BackgroundElevated levels of Prostaglandin E2 (PGE2), an eicosanoid notably synthesized by the cyclooxygenase-2 (COX-2), exert strong immunosuppressive effects in the tumor microenvironment. COX-2-positive solid tumors have the ability to use this pathway as a resistance mechanism, especially to escape from the host immune system, thus limiting the anti-tumor effects of immune checkpoint inhibitors (ICI). These immunosuppressive effects are largely mediated by the EP4 receptor, expressed on multiple immune cells.MethodsA novel series of EP4 receptor antagonists has been developed, with improved pharmacokinetic properties when compared to the EP4 receptor antagonists currently being evaluated in clinical trials. An intensive lead optimization program led to the identification of DT095895, a small molecule development candidate with a ‘best-in class’ potential. DT095895 was assessed in multiple syngeneic mouse tumor models selected for their COX-2 expression profile.ResultsDT095895 preclinical package will be presented in the poster. Efficacy was seen both in a monotherapy setting, as well as in combination with an ICI. Additionally, a specific biomarker program was implemented and validated in order to show target engagement. A phospho-flow murine whole blood assay was set-up to assess the ability of DT095895 to inhibit CREB phosphorylation induced by a selective EP4 receptor agonist in CD3+ cells. This biomarker was further developed for human whole blood to support Phase 1 and clinical trials studies.ConclusionsDT095895 is a selective EP4 receptor antagonist and demonstrates strong anti-tumor effects in multiple syngeneic mouse tumor models, both as a monotherapy and in combination with ICI, through the inhibition of the PGE2-induced immunosuppression. DT095895 progresses in regulatory development.

Abstract A114: Effect of different standard of care chemotherapeutics on anti-PD-L1 responses in syngeneic mouse tumor models

2016 ◽  
Author(s):  
Rafael Cubas ◽  
Marina Moskalenko ◽  
Jeanne Cheung ◽  
Shiuh-Ming Luoh ◽  
Erin McNamara ◽  
...  
Keyword(s):  
Standard Of Care ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Mouse Tumor Models

Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves

2004 ◽  
Vol 287 (6) ◽  
pp. F1269-F1282 ◽  
Author(s):  
Ulla C. Kopp ◽  
Michael Z. Cicha ◽  
Kazuhiro Nakamura ◽  
Rolf M. Nüsing ◽  
Lori A. Smith ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Prostaglandin E ◽  
Ep4 Receptor ◽  
Pelvic Wall ◽  
Ep4 Receptor Antagonist ◽  
Cox 2 ◽  
Ep3 Receptor ◽  
Stimulation Of

Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E2 (PGE2) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th9-L1 and in nerve terminals in the renal pelvic wall. Th9-L1 DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 μM) had no effect on SP release produced by PGE2 (0.14 μM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 μM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 μM) 12 ± 2 vs. 2 ± 1 and PGE2, 9 ± 1 vs. 1 ± 0 pg/min. The SP release by butaprost and PGE2 was similarly blocked by the EP4 receptor antagonist AH-23848 (30 μM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 ± 100 and PGE2·780 ± 100%·s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 μM L-161,982 and 10 μM AH-23848 blocked the ARNA responses to butaprost by 94 ± 5 and 78 ± 10%, respectively, and to PGE2 by 74 ± 16 and 74 ± 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 ± 5%. In conclusion, PGE2 increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.

Abstract 3765: An anti-CD137 antibody can show greater efficacy in syngeneic mouse tumor models when combined with other immuno-oncology (IO) therapies

2018 ◽  
Author(s):  
Matthew J. Robinson ◽  
Ines Osma-Garcia ◽  
Jane Coates-Ulrichisen ◽  
Amanda Watkins ◽  
Suzanne Mosely ◽  
...  
Keyword(s):  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Mouse Tumor Models

scholarly journals 573 FS120, an OX40/CD137 tetravalent bispecific dual agonist antibody, synergistically increases the antitumor activity of anti-PD-1 in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A602-A602
Author(s):  
Matthew Lakins ◽  
Wenjia Liao ◽  
Emma McConnell ◽  
Quincy Kaka ◽  
Jennifer Ofoedu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Bispecific Antibody ◽  
Cell Activity ◽  
T Cell Proliferation ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Tumor Bearing ◽  
Mouse Tumor Models

BackgroundImmune checkpoint inhibitors have demonstrated durable clinical responses and an increase in overall survival for some patients with cancer. Next generation cancer immunotherapies, such as tumor necrosis factor receptor superfamily (TNFRSF) agonists, have potential to further improve on this success. FS120 is a tetravalent bispecific antibody targeting OX40 and CD137 (4-1BB), currently being evaluated in a Phase I clinical trial (NCT04648202). FS120 activates CD4+ and CD8+ T cells by concurrent binding to both targets via an FcgR-independent mechanism [1]. In preclinical tumor models, FS120 induced T cell proliferation and cytokine production associated with significant tumor regression, better than that observed with a monoclonal antibody combination. Here, we demonstrate the ability of FS120 to improve anti-PD-1 induced T cell activity, increasing tumor growth inhibition and survival, in syngeneic mouse tumor models, compared to monotherapy.MethodsFS120 < i >in vitro</i > activity in combination with anti-PD-1 was assessed by utilizing staphylococcal enterotoxin A (SEA) superantigen assays and mixed leukocyte reaction (MLR) assays. An anti-mouse OX40/CD137 bispecific antibody (FS120 surrogate) was tested in CT26 syngeneic mouse tumor models in combination with an anti-mouse PD-1 antibody to assess efficacy and pharmacodynamic endpoints, including T cell proliferation by < i>ex vivo</i> flow cytometry and serum cytokine levels.ResultsFS120 in combination with anti-PD-1 enhanced primary human T cell activity, when compared to either monotherapy, in both SEA and MLR assays. FS120 surrogate significantly improved survival of CT26 tumor-bearing mice treated with anti-mPD-1 antibody. FS120 surrogate and anti-PD-1 combination significantly enhanced serum interferon-gamma levels and increased proliferating granzyme B+ CD8+ T cells in the blood of tumor-bearing mice, when compared to either monotherapy treatments.ConclusionsFS120 combination with anti-PD-1 enhances T cell activity in multiple human primary immune assays. In combination with anti-PD-1, FS120 surrogate increased the antitumor efficacy with pharmacodynamic changes related specifically to T cell activation, when compared to monotherapies. These data support the development of FS120 in combination with anti-PD-1 in patients with hard-to-treat cancers who may not benefit fully from either treatment as a monotherapy.ReferencesGaspar M, Pravin J, Rodrigues L, Uhlenbroich S, Everett K L, Wollerton F, Morrow M, Tuna M, Brewis N. CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement. Cancer Immunol Res. 2020; (8) (6) 781–793Ethics ApprovalMurine studies were conducted under a U.K. Home Office License in accordance with the U.K. Animal (Scientific Procedures) Act 1986 and EU Directive EU 2010/63.

scholarly journals Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models

2019 ◽  
Vol 8 (5) ◽  
pp. e1558678 ◽  
Author(s):  
Adrienne Rothschilds ◽  
Alice Tzeng ◽  
Naveen K. Mehta ◽  
Kelly D. Moynihan ◽  
Darrell J. Irvine ◽  
...  
Keyword(s):  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Order Of Administration ◽  
Mouse Tumor Models
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