scholarly journals Caffeic Acid Inhibits NFkappaB Activation of Osteoclastogenesis Signaling Pathway

2011 ◽  
Vol 3 (3) ◽  
pp. 216 ◽  
Author(s):  
Ferry Sandra ◽  
Toshio Kukita ◽  
Quan Yong Tang ◽  
Tadahiko Iijima
Keyword(s):  
Caffeic Acid ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Luciferase Reporter ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
D Cells ◽  
Dose Dependent

BACKGROUND: Caffeic acid (3,4-dihydroxycinnamic acids) is involved in various green plants. Based on our previous report, a major component of sweet potato extracts, possibly caffeic acid, was shown as a promising inhibitor of osteoclastogenesis. However, the effect of caffeic acid in inhibiting osteoclastogenesis needs to be confirmed. The underlying mechanism needs to be disclosed as well.METHODS: Caffeic acid in various concentrations was added to in vitro osteoclastogenesis of receptor activator nuclear factor kB ligand (RANKL)-tumor necrosis factor alpha (TNF-α)-macrophage colony stimulating factor (M-CSF)-induced bone marrow-derived monocyte/macrophage precursor cells (BMMs) and RANKL-TNF-α-induced RAW264 cells D-Clone (RAW-D cells). Tartrate resistant acid phosphatase (TRAP) staining was performed and TRAP-positive polynucleated cells (PNCs) were counted. For apoptosis analysis, caffeic acid-treated BMMs, RAW-D cells and osteoclast-like PNCs were subjected to Sub-G1 Apoptosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. To measure NFkB activity, RAW-D cells were transfected with pNFkB-TA-Luc and subjected to Dual Luciferase Reporter Assay System.RESULTS: Caffeic acid inhibited osteoclastogenesis of RANKL-TNF-α-M-CSF-induced BMMs as well as RANKL-TNF-α-induced RAW-D cells in a dose dependent manner. Caffeic acid did not induce apoptosis in BMMs, RAW-D cells and osteoclast-like PNCs. RANKL-TNF-α-induced NFkB activity in RAW-D was diminished by caffeic acid in a dose dependent manner. Significant NFkB activity inhibtion was observed starting from 1 µg/mL caffeic acid. CONCLUSIONS: Caffeic acid could be a potent osteoclastogenesis inhibitor through inhibition of NFkB activity. Our present study should be further followed up to disclose caffeic acid's possible overlying signaling pathways in inhibiting osteoclastogenesis.KEYWORDS: caffeic acid, osteoclastogenesis, NFkB, RANKL, TNF-α

scholarly journals Effects of Caffeoylquinic Acid Derivatives and C-Flavonoid from Lychnophora ericoides on in vitro Inflammatory Mediator Production

2010 ◽  
Vol 5 (5) ◽  
pp. 1934578X1000500 ◽  
Author(s):  
Michel David dos Santos ◽  
Guanjie Chen ◽  
Maria Camila Almeida ◽  
Denis Melo Soares ◽  
Glória Emília Petto de Souza ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Cultured Cells ◽  
Dependent Manner ◽  
Caffeoylquinic Acid ◽  
Inflammatory Mediator Production ◽  
Dicaffeoylquinic Acid ◽  
Tnf Α ◽  
Dose Dependent Fashion ◽  
Dose Dependent

In this study we aimed at evaluating the effect of the major polar constituents of the medicinal plant Lychnophora ericoides on the production of inflammatory mediators produced by LPS-stimulated U-937 cells. The 6,8-di- C-β-glucosylapigenin (vicenin-2) presented no effect on tumor necrosis factor (TNF)-α production, but inhibited, in a dose-dependent manner, the production of prostaglandin (PG) E2 without altering the expression of cyclooxygenase (COX) -2 protein. 3,5-Dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid, at lower concentrations, had small but significant effects on reducing PGE2 levels; at higher doses these compounds stimulated PGE2 and also TNF-α production by the cells. All the caffeoylquinic acid derivatives, in a dose-dependent fashion, were able to inhibit monocyte chemoattractant protein-3 synthesis/release, with 4,5-DCQ being the most potent at the highest tested concentration. These results add important information on the effects of plant natural polyphenols, namely vicenin-2 and caffeoylquinic acid derivatives, on the production of inflammatory mediators by cultured cells.

scholarly journals Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

2001 ◽  
Vol 69 (4) ◽  
pp. 2025-2030 ◽  
Author(s):  
Shuhua Yang ◽  
Shunji Sugawara ◽  
Toshihiko Monodane ◽  
Masahiro Nishijima ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Lipid A ◽  
Micrococcus Luteus ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Monocytic Cells ◽  
Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

scholarly journals Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

2004 ◽  
Vol 11 (6) ◽  
pp. 1140-1147 ◽  
Author(s):  
Hidenori Matsuzaki ◽  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyoshi Wakahara ◽  
Toshiharu Kondo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

Protein-free phospholipid emulsion treatment improved cardiopulmonary function and survival in porcine sepsis

2003 ◽  
Vol 284 (2) ◽  
pp. R550-R557 ◽  
Author(s):  
Roy D. Goldfarb ◽  
Thomas S. Parker ◽  
Daniel M. Levine ◽  
Dana Glock ◽  
Imran Akhter ◽  
...  
Keyword(s):  
Density Lipoprotein ◽  
Fibrin Clot ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Serum Lipoproteins ◽  
Treatment Groups ◽  
Tnf Α ◽  
Dose Dependent

Lipoprotein phospholipid (PL) plays a major role in neutralization of endotoxin. This study tested the hypothesis that prophylactic administration of a PL-enriched emulsion (PRE), which augments PL content of serum lipoproteins and neutralizes endotoxin in vitro, would preserve cardiovascular function and improve survival in porcine septic peritonitis. A control group was compared with low-, mid-, and high-dose treatment groups that received PRE by primed continuous infusion for 48 h. A fibrin clot containing live Escherichia coli 0111.B4 was implanted intraperitoneally 30 min after the priming dose. Survival increased in a dose-dependent manner and was correlated with serum PL. Infused PL was associated with high-density lipoprotein in the low-dose group and all serum lipoproteins at higher doses. Treatment significantly lowered serum endotoxin and tumor necrosis factor (TNF)-α, preserved cardiac output and ejection fraction, and attenuated increases in systemic and pulmonary vascular resistances. This study demonstrated that augmentation of lipoprotein PL via administration of PRE improved survival and offered a novel therapeutic approach to sepsis.

scholarly journals A Dairy Bacterium Displays InVitro Probiotic Properties for the Pharyngeal Mucosa by Antagonizing Group A Streptococci and Modulating the Immune Response

2010 ◽  
Vol 78 (11) ◽  
pp. 4734-4743 ◽  
Author(s):  
Simone Guglielmetti ◽  
Valentina Taverniti ◽  
Mario Minuzzo ◽  
Stefania Arioli ◽  
Ivan Zanoni ◽  
...  
Keyword(s):  
Immune Response ◽  
The Body ◽  
Lactobacillus Helveticus ◽  
Hypopharyngeal Carcinoma ◽  
Probiotic Properties ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α

ABSTRACT The probiotic approach represents an alternative strategy in the prevention and treatment of infectious diseases, not only at the intestinal level but also at other sites of the body where the microbiota plays a role in the maintenance of physiological homeostasis. In this context, we evaluated in vitro the potential abilities of probiotic and dairy bacteria in controlling Streptococcus pyogenes infections at the pharyngeal level. Initially, we analyzed bacterial adhesion to FaDu hypopharyngeal carcinoma cells and the ability to antagonize S. pyogenes on FaDu cell layers and HaCat keratinocytes. Due to its promising adhesive and antagonistic features, we studied the dairy strain Lactobacillus helveticus MIMLh5, also through in vitro immunological experiments. First, we performed quantification of several cytokines and measurement of NF-κB activation in FaDu cells. MIMLh5 efficiently reduced the induction of interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α), in a dose-dependent manner. After stimulation of cells with IL-1β, active NF-κB was still markedly lowered. Nevertheless, we observed an increased secretion of IL-6, gamma interferon (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) under these conditions. These effects were associated with the ability of MIMLh5 to enhance the expression of the heat shock protein coding gene hsp70. In addition, MIMLh5 increased the GM-CSF/G-CSF ratio. This is compatible with a switch of the immune response toward a TH1 pathway, as supported by our observation that MIMLh5, once in contact with bone marrow-derived dendritic cells, triggered the secretion of TNF-α and IL-2. In conclusion, we propose MIMLh5 as a potential probiotic bacterium for the human pharynx, with promising antagonistic and immunomodulatory properties.

Zoledronic Acid Inhibits Osteoclastogenesis in Vitro and in a Mouse Model of Inflammatory Osteolysis

2003 ◽  
Vol 112 (9) ◽  
pp. 780-786 ◽  
Author(s):  
Holger Sudhoff ◽  
Brian T. Faddis ◽  
Jae Y. Jung ◽  
Henning Hildmann ◽  
Jörg Ebmeyer ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Marrow Cells ◽  
Mineral Apposition Rate ◽  
Tunel Staining ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mouse Bone Marrow ◽  
Dependent Manner ◽  
Dose Dependent

This study assessed effects of the bisphosphonate zoledronic acid (ZLNA) on osteoclastogenesis. To assess the effect of ZLNA on osteoclast formation in vitro, we cultured mouse bone marrow cells under conditions that promote osteoclastogenesis. Administered at concentrations from 10−6 to 10−9 mol/L, ZLNA led to a dose-dependent inhibition of osteoclastogenesis. Combined TUNEL staining and histochemical staining for tartrate-resistant acid phosphatase showed that ZLNA induced apoptosis in osteoclasts and monocytic precursor cells. To study the effects of ZLNA in vivo, we placed keratin particles onto the surface of the parietal bone of mice to induce localized inflammatory bone resorption. Three experimental groups received daily subcutaneous injections of ZLNA (1, 3, or 10 μg/kg body weight) from 4 days before surgery until 5 days after keratin implantation. The ZLNA significantly reduced osteoclast recruitment in a dose-dependent manner, but did not affect the degree of inflammation or the mineral apposition rate.

scholarly journals Repression of Ets-2-Induced Transactivation of the Tau Interferon Promoter by Oct-4

2001 ◽  
Vol 21 (23) ◽  
pp. 7883-7891 ◽  
Author(s):  
Toshihiko Ezashi ◽  
Debjani Ghosh ◽  
R. Michael Roberts
Keyword(s):  
Luciferase Reporter ◽  
Dependent Manner ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Pou Domain ◽  
Choriocarcinoma Cells ◽  
A Site ◽  
Dose Dependent ◽  
Developmental Switch

ABSTRACT Oct-4 is a POU family transcription factor associated with potentially totipotent cells. Genes expressed in the trophectoderm but not in embryos prior to blastocyst formation may be targets for silencing by Oct-4. Here, we have tested this hypothesis with the tau interferon genes (IFNT genes), which are expressed exclusively in the trophectoderm of bovine embryos. IFNTpromoters contain an Ets-2 enhancer, located at −79 to −70, and are up-regulated about 20-fold by the overexpression of Ets-2 in human JAr choriocarcinoma cells, which are permissive for IFNTexpression. This enhancement was reversed in a dose-dependent manner by coexpression of Oct-4 but not either Oct-1 or Oct-2. When cells were transfected with truncated bovine IFNT promoters designed to eliminate potential octamer sites sequentially, luciferase reporter expression from each construct was still silenced by Oct-4. Full repression required both the N-terminal and POU domains of Oct-4, but neither domain used alone was an effective silencer. Oct-4 and Ets-2 formed a complex in vitro in the absence of DNA through binding of the POU domain of Oct-4 to a site located between the “pointed” and DNA binding domains of Ets-2. The two transcription factors were also coimmunoprecipitated after being expressed together in JAr cells. Oct-4, therefore, silences IFNT promoters by quenching Ets-2 transactivation. The POU domain most probably binds to Ets-2 directly, while the N-terminal domain inhibits transcription. These findings provide further evidence that the developmental switch to the trophectoderm is accompanied by the loss of Oct-4 silencing of key genes.

scholarly journals Theiler's Murine Encephalomyelitis Virus Induces Apoptosis in Gamma Interferon-Activated M1 Differentiated Myelomonocytic Cells through a Mechanism Involving Tumor Necrosis Factor Alpha (TNF-α) and TNF-α-Related Apoptosis-Inducing Ligand

2001 ◽  
Vol 75 (13) ◽  
pp. 5930-5938 ◽  
Author(s):  
Mary Lou Jelachich ◽  
Howard L. Lipton
Keyword(s):  
Virus Replication ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Encephalomyelitis Virus ◽  
Factor Alpha ◽  
Ifn Γ ◽  
D Cells ◽  
Necrosis Factor

ABSTRACT Infection of susceptible mice with the low-neurovirulence Theiler's murine encephalomyelitis virus strain BeAn results in an inflammatory demyelinating disease similar to multiple sclerosis. While the majority of virus antigen is detected in central nervous system macrophages (Mφs), few infiltrating Mφs are infected. We used the myelomonocytic precursor M1 cell line to study BeAn virus-Mφ interactions in vitro to elucidate mechanisms for restricted virus expression. We have shown that restricted BeAn infection of M1 cells differentiated in vitro (M1-D) results in apoptosis. In this study, BeAn infection of gamma interferon (IFN-γ)-activated M1-D cells also resulted in apoptosis but with no evidence of virus replication or protein expression. RNase protection assays of M1-D cellular RNA revealed up-regulation of Fas and the p55 chain of the tumor necrosis factor alpha (TNF-α) receptor transcripts with IFN-γ activation. BeAn infection of activated cells resulted in increased caspase 8 mRNA transcripts and the appearance of TNF-α-related apoptosis-inducing ligand (TRAIL) 4 h postinfection. Both unactivated and activated M1-D cells expressed TRAIL receptors (R1 and R2), but only activated cells were killed by soluble TRAIL. Activated cells were also susceptible to soluble FasL- and TNF-α-induced apoptosis. The data suggest that IFN-γ-activated M1-D cell death receptors become susceptible to their ligands and that the cells respond to BeAn virus infection by producing the ligands TNF-α and TRAIL to kill the susceptible cells. Unactivated cells are not susceptible to FasL or TRAIL and require virus replication to initiate apoptosis. Therefore, two mechanisms of apoptosis induction can be triggered by BeAn infection: an intrinsic pathway requiring virus replication and an extrinsic pathway signaling through the death receptors.

scholarly journals Suppression of Murine Endotoxin Response by E5531, a Novel Synthetic Lipid A Antagonist

1998 ◽  
Vol 42 (11) ◽  
pp. 2824-2829 ◽  
Author(s):  
Seiichi Kobayashi ◽  
Tsutomu Kawata ◽  
Akifumi Kimura ◽  
Kaname Miyamoto ◽  
Koichi Katayama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lipid A ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
In Vivo Models ◽  
Lps Challenge ◽  
Tnf Α

ABSTRACT As a consequence of blood-borne bacterial sepsis, endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria can trigger an acute inflammatory response, leading to a series of pathological events and often resulting in death. To block this inflammatory response to endotoxin, a novel lipid A analogue, E5531, was designed and synthesized as an LPS antagonist, and its biological properties were examined in vitro and in vivo. In murine peritoneal macrophages, E5531 inhibited the release of tumor necrosis factor alpha (TNF-α) by Escherichia coli LPS with a 50% inhibitory concentration (IC50) of 2.2 nM, while E5531 elicited no significant increases in TNF-α on its own. In support of a mechanism consistent with antagonism of binding to a cell surface receptor for LPS, E5531 inhibited equilibrium binding of radioiodinated LPS ([125I]2-(r-azidosalicylamido)-1, 3′-dithiopropionate-LPS) to mouse macrophages with an IC50 of 0.50 μM. E5531 inhibited LPS-induced increases in TNF-α in vivo when it was coinjected with LPS into C57BL/6 mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this model, the efficacy of E5531 was inversely correlated to the LPS challenge dose, consistent with a competitive antagonist-like mechanism of action. Blockade of the inflammatory response by E5531 could further be demonstrated in other in vivo models: E5531 protected BCG-primed mice from LPS-induced lethality in a dose-dependent manner and suppressed LPS-induced hepatic injury in Propionibacterium acnes-primed or galactosamine-sensitized mice. These results argue that the novel synthetic lipid A analogue E5531 can antagonize the action of LPS in in vitro and suppress the pathological effects of LPS in vivo in mice.

633 Dual-targeting of 4–1BB and OX40 with an ADAPTIR™ bispecific antibody enhances anti-tumor responses to solid tumor

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A669-A669
Author(s):  
Michelle Nelson ◽  
Robert Miller ◽  
Gabriele Blahnik-Fagan ◽  
Lauren Loh ◽  
Danielle Van Citters ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Bispecific Antibody ◽  
Cytokine Production ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Binding Domains ◽  
Dose Dependent

Background4-1BB (CD137) and OX40 (CD134) are critical activation-induced co-stimulatory receptors that regulate immune responses of activated T and NK cells by enhancing proliferation, cytokine production, survival, and cytolytic activity. A superagonist 4-1BB antibody has shown clinical activity but severe toxicities. APVO603, is a 4-1BB x OX40 targeting bispecific antibody with conditional agonism, activating these receptors only when both are co-engaged. The Fc portion was mutated to eliminate FcγR-mediated interactions. Co-stimulation through 4-1BB and OX40 has the potential to amplify the cytotoxic function and the number of activated T and NK cells in multiple solid tumor indications.1–2Methods scFv binding domains to 4-1BB and OX40 were optimized to increase affinity, function and stability, and then incorporated into the ADAPTIR™ bispecific antibody platform to produce the APVO603 lead candidate. NF-κB/luciferase reporter cell lines expressing OX40 or 4-1BB were initially used to assess the agonistic function of APVO603’s binding domains. Primary PBMC were sub-optimally stimulated with an anti-CD3 antibody and T and NK cell proliferation was assessed using Cell TraceTM-labelled PBMC. Cytokine secretion was measured at 48 hrs using Luminex-based assays. For in vitro tumor lysis studies, PBMC were co-cultured with tumor cells expressing a tumor-associated antigen (TAA) and activated with TAA x CD3 bispecific protein. 7-AAD expression was assessed on tumor cells at 72 hrs. The in vivo therapeutic efficacy of APVO603 was evaluated using a murine MB49 bladder cancer model in human 4-1BB and OX40 double knock-in mice.ResultsAPVO603 stimulates 4-1BB and OX40 NF-κB/luciferase reporter activity in a dose-dependent manner, and is strictly dependent on engagement of the reciprocal receptor to elicit 4-1BB or OX40 activity. In primary PBMC assays, APVO603 induces synergistic proliferation of CD4+, CD8+ T and NK cells when compared to OX40 or 4-1BB monospecific molecules with a wt Fc, either individually or in combination. Additionally, APVO603 enhances proinflammatory cytokine production and granzyme B expression, and augments in vitro tumor cell lysis induced by a TAAx CD3 engager. In vivo, APVO603 reduces growth of established MB49 tumors in human 4-1BB and OX40 double knock-in mice.ConclusionsAPVO603 is a dual-agonistic bispecific antibody that augments the effector function of activated CD4+ and CD8+ T and NK cells in a dose-dependent manner, and reduces growth of established tumors in vivo. This preclinical data, demonstrates conditional dual stimulation of 4-1BB and OX40 and supports further development of APVO603, a promising immuno-oncology therapeutic with potential for benefit in solid tumors.Ethics ApprovalTreatment of study animals was in accordance with conditions specified in the Guide for the Care and Use of Laboratory Animals, and the study protocol (ACUP 20) was approved by the Institutional Animal Care and Use Committee (IACUC).ReferencesBandyopadhyay S, Long M, Qui H, Hagymasi A, Slaiby A, Mihalyo M, Aguila H, Mittler R, Vella A, Adler A. Self-antigen prevents CD8 T cell effector differentiation by CD134 and CD137 dual costimulation. J Immunol 2008;181(11):7728–37.Ryan J, Mittal P, Menoret A, Svedova J, Wasser J, Adler A, Vella A. A novel biologic platform elicits profound T cell costimuloaroty activity and antitumor immunity in mice. Cancer Immunol Immunother 2018;67(4):605–613.

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