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 A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Eric J. Smith ◽  
Kara Olson ◽  
Lauric J. Haber ◽  
Bindu Varghese ◽  
Paurene Duramad ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Bispecific Antibody ◽  
Cell Killing ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Cynomolgus Monkeys ◽  
Mouse Tumor Models

scholarly journals PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

2017 ◽  
Vol 1 (12) ◽  
pp. 753-765 ◽  
Author(s):  
Natalie A. Bezman ◽  
Amy Jhatakia ◽  
Alper Y. Kearney ◽  
Ty Brender ◽  
Mark Maurer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Mouse Models ◽  
Cell Activity ◽  
Antitumor Efficacy ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Key Points ◽  
Mouse Tumor Models

Key PointsThe combination of elotuzumab and an anti–PD-1 antibody leads to enhanced antitumor efficacy in mouse models. Enhanced antitumor activity is likely due to the promotion of tumor-infiltrating NK and T-cell activity.

scholarly journals 843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A884-A884
Author(s):  
Li Peng ◽  
Lizhi Cao ◽  
Sujata Nerle ◽  
Robert LeBlanc ◽  
Abhishek Das ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
First Generation ◽  
Single Agent ◽  
Mouse Tumor ◽  
Cytokine Release ◽  
Tumor Models ◽  
Cell Immunity ◽  
Mouse Tumor Models

BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model

2018 ◽  
Vol 6 (10) ◽  
pp. 1199-1211 ◽  
Author(s):  
Simran S. Sabharwal ◽  
David B. Rosen ◽  
Jeff Grein ◽  
Dana Tedesco ◽  
Barbara Joyce-Shaikh ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cytokine Production ◽  
Cellular Metabolism ◽  
Tumor Model ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Mouse Tumor ◽  
Mouse Tumor Model ◽  
Effector Cytokine

Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3019-3019 ◽  
Author(s):  
Maria Jure-Kunkel ◽  
Mark Selby ◽  
Katherine Lewis ◽  
Gregg Masters ◽  
Jose Valle ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Nk Cell ◽  
Phase Iii ◽  
Tumor Growth Inhibition ◽  
Clinical Activity ◽  
Mouse Tumor ◽  
Synergistic Activity ◽  
Tumor Models ◽  
Mouse Tumor Models

3019 Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9-IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 μg/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 μg/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p=0.046). CTLA-4 mAb + mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p<0.05). Conclusions: These results support the use of rIL-21+nivolumab and rIL-21+ipilimumab in recently initiated clinical trials.

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

scholarly journals Myeloid-derived suppressor cells are bound and inhibited by anti-thymocyte globulin

2019 ◽  
Vol 25 (1) ◽  
pp. 46-59 ◽  
Author(s):  
Young Suk Lee ◽  
Eduardo Davila ◽  
Tianshu Zhang ◽  
Hugh P Milmoe ◽  
Stefanie N Vogel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Arginase Activity ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
And Function

Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin (ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1 tumor-bearing mice. MDSC development and function were assessed in vivo and in vitro with and without ATG administration. T cell suppression assays, RT-PCR, flow cytometry and arginase activity assays were used to assess MDSC phenotype and function. MDSCs increased dramatically in tumor-bearing mice and the majority of splenic MDSCs were of the polymorphonuclear subset. MDSCs potently suppressed T cell proliferation. ATG-treated mice developed 50% fewer MDSCs and these MDSCs were significantly less suppressive of T cell proliferation. In vitro, ATG directly bound 99.6% of MDSCs. CCR7, L-selectin and LFA-1 were expressed by both T cells and MDSCs, and binding of LFA-1 was inhibited by ATG pre-treatment. Arg-1 and PD-L1 transcript expression were reduced 30–40% and arginase activity decreased in ATG-pretreated MDSCs. MDSCs were bound and functionally inhibited by ATG. T cells and MDSCs expressed common Ags which were also targets of ATG. ATG may be helpful in tumor models seeking to suppress MDSCs. Alternatively, ATG may inadvertently inhibit important T cell regulatory events in autoimmunity and transplantation.

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