Anti-CD137 Antibodies in the Treatment of Autoimmune Disease and Cancer

Mittler, Robert S.; Foell, Juergen; McCausland, Megan; Strahotin, Simona; Niu, Liguo; Bapat, Abhijit S.; Hewes, L. Becker

doi:10.1385/ir:29:1-3:197

Cited by 55 publications

(40 citation statements)

References 27 publications

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“…Agonist monoclonal antibodies (mAb) directed to anti-CD137 or multivalent RNA aptamers binding CD137 (12) have been shown to therapeutically enhance antitumor CD8 T-cellmediated immunity in mice (3,(13)(14)(15). Interestingly, treatment with agonist anti-CD137 mAb can overcome tumor antigen tolerance (16) in a number of models and more importantly, can be successfully combined with both other immunotherapeutic strategies (17)(18)(19)(20) and conventional immune-unrelated treatment approaches (17,21).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism of action has been interpreted in the sense that a stronger CD8 T-cell-mediated immune response is artificially costimulated in treated animals (3,13,29). Direct stimulation of the CD137 receptor on T cells is definitely involved in the immunotherapeutic effects, but the interaction of the agonist antibodies with CD137 expressed on the surface of activated NK cells (15,30) and dendritic cells (5) can also be of importance (3).…”

Section: Introductionmentioning

confidence: 99%

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Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

et al. 2011

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Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag À/À mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies. Cancer Res; 71(3); 801-11. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

et al. 2011

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“…Consequently a number of reports have addressed the role of members of the TNFR/TNF families on antigen-experienced T cells and have demonstrated potent and important costimulatory functions for these molecules on virus-specific human T cells [8][9][10][11]. Thus blocking or enhancing costimulatory TNF/TNFR family molecule interactions has been discussed as promising therapeutic avenue in host defense, autoimmunity, cancer and transplantation-associated pathologies [12][13][14]. However, costimulatory TNFR family members, which are either constitutively expressed on primary T cells or quickly induced upon activation, can also effectively costimulate primary human T cells.…”

Section: Introductionmentioning

confidence: 99%

The capacity of the TNF family members 4‐1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells

et al. 2008

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Activating signals generated by members of the tumour necrosis factor receptor superfamily upon interaction with their cognate ligands play important roles in T-cell responses. Members of the tumour necrosis factor family namely 4-1BBL, OX40L, CD70, GITRL, LIGHT and CD30L have been described to function as costimulatory molecules by binding such receptors on T cells. Using our recently described system of T-cell stimulator cells we have performed the first study where all these molecules have been assessed and compared regarding their capacity to costimulate proliferation and cytokine production of human T cells. 4-1BBL, which we found to be the most potent molecule in this group, was able to mediate sustained activation and proliferation of human T cells. OX40L and CD70 were also strong inducers of T-cell proliferation, whereas the costimulatory capacity of human GITRL was significantly lower. Importantly CD30L and LIGHT consistently failed to act costimulatory on human T cells, and we therefore suggest that these molecules might be functionally distinct from the costimulatory members of this family.Key words: Cell activation . Costimulation . Costimulatory molecules . T cells IntroductionEfficient T-cell activation requires two different signals, provided by MHC-TCR interaction (signal 1) and additional receptorligand interactions that give a costimulatory signal (signal 2) to T cells [1]. Interaction of the immunoglobulin superfamily members CD80/86-CD28 and ICOSL-ICOS can efficiently costimulate proliferation, cytokine production and effector cell generation of T cells [2]. Another group of costimulatory molecules is comprised by members of the tumour necrosis factor receptor (TNFR) superfamily, which can costimulate TCR signals upon interaction with their cognate ligands, members of TNF super-family. Costimulation of T-cell activation has been reported for several members of the TNFR/TNF superfamilies namely for 4-1BB-4-1BBL, OX40-OX40L, CD27-CD70, GITR-GITRL, herpes virus entry mediator (HVEM)-LIGHT and 2678CD30-CD30L [3,4]. Interaction of these TNF family ligands with their receptors leads to recruitment of TNFR-associated factors (TRAF), which initiate signalling cascades that result in T-cell activation. All these TNFR can recruit TRAF2 but there are differences between these molecules in the recruitment of other TRAF proteins [5].Although there is extensive literature on costimulatory pathways involving human 4-1BBL, OX40L and CD70, few reports have described costimulatory functions for human LIGHT and CD30L [6,7]. Signals transduced by members of the TNFR family are regarded as especially important for survival, expansion and effector function of T cells that have initially received activating signals via the CD28 receptor [4]. Consequently a number of reports have addressed the role of members of the TNFR/TNF families on antigen-experienced T cells and have demonstrated potent and important costimulatory functions for these molecules on virus-specific human T cells [8][9][10][11]. Thus blocking or ...

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“…Growing evidence also suggests that signals relayed through the CD137 receptor amplify CD8 responses (7). CD137-mediated activation is distinct from and independent of CD28 and is known to involve members of the TNFR-associated factor family leading to activation of various kinases, such as apoptosis signal-regulating kinase, MAPK kinase, MAPK3/MAPK4, p38, and JNK/stress-activated protein kinase, eventually to culminate in the activation and nuclear translocation of several transcription factors, namely ATF-2, Jun, and NF-B (8).…”

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confidence: 99%

CD137-Deficient Mice Have Reduced NK/NKT Cell Numbers and Function, Are Resistant to Lipopolysaccharide-Induced Shock Syndromes, and Have Lower IL-4 Responses

Vinay

Choi

Bae

et al. 2004

The Journal of Immunology

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CD137, a member of the TNF superfamily, is involved in T cell and NK cell activation and cytokine production. To establish its in vivo role in systems dependent on NK and NKT cells, we studied the response of CD137−/− mice to LPS-induced shock, tumor killing, and their IL-4-controlled Th2 responses. In both high and low dose shock models, all the CD137-deficient mice, but none of the wild-type BALB/c mice, survived. After injection of LPS/2-amino-2-deoxy-d-galactose (D-gal), CD137−/− mice had reduced serum cytokine levels and substantially impaired liver IFN-γ and TNF-α mRNA levels. Phenotypic analysis of mononuclear cells revealed fewer NK and NKT cells in the CD137−/− mice. The knockout mice did not generate a rapid IL-4 response after systemic T cell activation, or effective Ag-specific Th2 responses. In addition, both in vitro and in vivo NK-specific cytolytic activities were reduced. These findings suggest that CD137-directed NK/NKT cells play an important role in the inflammatory response leading to the production of proinflammatory cytokines, LPS-induced septic shock, and tumor killing, as well as IL-4-dependent Th2 responses.

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Anti-CD137 Antibodies in the Treatment of Autoimmune Disease and Cancer

Cited by 55 publications

References 27 publications

Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

The capacity of the TNF family members 4‐1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells

CD137-Deficient Mice Have Reduced NK/NKT Cell Numbers and Function, Are Resistant to Lipopolysaccharide-Induced Shock Syndromes, and Have Lower IL-4 Responses

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