A phase I study of the GM-CSF antagonist E21R

Olver, Ian; Hercus, Timothy R.; Lopez, Angel F.; Vadas, MA; Somogyi, Andrew A.; Doyle, Ian; Foster, David J. R.; Keefe, Dorothy; Taylor, Anne L.; Brown, Michael P.; To, LB; Cole, Julie; Rawling, T.; Cambareri, Bronwyn; Myers, Melinda; Olszewski, Nancy A; Bastiras, Stan; Senn, Carol; Hey, A. W.; Verma, Meera; Wigley, Peter L.

doi:10.1007/s00280-002-0474-y

Cited by 10 publications

(7 citation statements)

References 19 publications

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“…In this regard, it is interesting to note that clinical trials are currently under way with various ligands and antagonists and chemokine receptors; furthermore, the elucidation of the crystal structure of the GM-CSFR complex holds promise for developing small molecule drugs which inhibit GM-CSFR-mediated functions in context of tumor–nerve interactions [75]. One antagonist of the GM-CSF receptor, E21R [76], has already been tested in clinical trials for the treatment of solid tumors [77]. The effects of E21R on cancer pain, however, were not investigated.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Hematopoietic colony-stimulating factors: new players in tumor–nerve interactions

2010

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A variety of cancers are accompanied by debilitating pain, which constitutes the primary reason for poor quality of life in cancer patients. There is an urgent demand for the development of specific mechanism-based therapies against cancer pain. Recently, important advances have been made in mechanisms contributing to cancer pain. A notable finding was that the tumor-derived hematopoietic growth factors, granulocyte- and granulocyte-macrophage-colony-stimulating factors (G-CSF/GM-CSF), subserve important functions in the generation of pain hypersensitivity in tumor-affected regions. In this context, their receptors were unexpectedly found on pain-sensing nerves and were observed to be functionally linked to nociceptive sensitization and tumor-induced pain. Here, we review evidence supporting a role for G-/GM-CSF in sensitization of pain-sensing nerves, the underlying signaling pathways and the cross-talk with other pronociceptive cytokines, peptides and modulators derived from immune cells, osteoclasts and tumor cells. These findings hold implications in the therapy of pain in disease states, such as cancer and rheumatoid arthritis.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Hematopoietic colony-stimulating factors: new players in tumor–nerve interactions

2010

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“…Apparently, multiple pathways are in control of eosinophilia. Interesting in this regard is the finding that treatment with GM‐CSF induces eosinophilia but only transiently . Nonetheless, these data implicate that discontinuation of the anti‐IL‐5 therapy should always be well monitored, because in some patients, aggravation of symptoms has been described, particularly when steroids were tapered before cessation of the IL‐5(Rα)‐targeted therapy …”

Section: Effect Of Il‐5(rα)‐targeted Therapy On Il‐5 Levels In Blood mentioning

confidence: 99%

Immunological and hematological effects of IL‐5(Rα)‐targeted therapy: An overview

Hassani

Koenderman

2018

Allergy

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IL‐5 is an important cytokine for priming and survival of mature eosinophils and for proliferation and maturation of their progenitors. Hence, IL‐5(Rα) targeting will be increasingly used in diseases where eosinophils are the key immune effector cells such as eosinophilic asthma (EA), hypereosinophilic syndrome (HES), eosinophilic esophagitis (EE), and eosinophilic granulomatosis with polyangiitis (EGPA). Therefore, several neutralizing monoclonal antibodies directed against IL‐5 (mepolizumab and reslizumab) and its receptor IL‐5Rα (benralizumab) have found or will find their way to the clinic. While the clinical effect of these drugs has been extensively investigated and reviewed, the understanding of the underlying immunological and hematological mechanisms remains less clear. This review will discuss the translational outcomes of treatment with these monoclonal antibodies in humans to shed light on the mechanisms underlying the main immunological and hematological findings from these clinical trials in humans.

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“…Next we investigated the effect of three GM-CSF blocking molecules: the neutralising monoclonal antibodies 4D4 and 4A12 and the GM-CSF antagonist E21R, [33][34][35] as well as the chemotherapeutic agents, Gem, 5FU and Sun, on the myeloid cell phenotype of cells grown in MDSC differentiation cultures containing IL-6 and GM-CSF. After performing titrations of each agent in culture we found substantial toxicity of Sun above 1 μM, Gem and 5FU above 10 μM and E21R above 10 μg ml − 1 , and so excluded these concentrations from further analysis.…”

Section: Effects Of Gm-csf-signalling Blockade and Chemotherapeutic Amentioning

confidence: 99%

“…Effects on circulating leukocyte subsets were observed, and transient reductions in serum PSA levels were observed in two prostate cancer patients. 35 We have also developed the GM-CSF-neutralising monoclonal antibodies 4D4 and 4A12 that block human GM-CSF activity in vitro. 36,37 Thus, E21R and the neutralising monoclonal antibodies 4D4 and 4A12 may be able to interfere with GM-CSF-dependent generation of MDSC.…”

mentioning

confidence: 99%

GM‐CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid‐derived suppressor cells in vitro

et al. 2016

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Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune-targeted treatment by promoting an immune-suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid-derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes. Pancreatic cancer in particular supports MDSC differentiation via the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), and MDSC are believed to contribute to the profoundly immune-suppressive microenvironment present in pancreatic tumours. MDSC-targeted therapies that deplete or inhibit this cell population have been proposed as a way to shift the balance in favour of a tumour-clearing immune response. In this study, we have modelled MDSC differentiation and function in vitro and this has provided us with the opportunity to test a range of potential MDSC-targeted therapies to identify candidates for further investigation. Using in vitro modelling we show here that the combination of GM-CSF-signalling blockade and gemcitabine suppresses both the MDSC phenotype and the inhibition of T-cell function by MDSC.

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A phase I study of the GM-CSF antagonist E21R

Abstract: E21R can be safely given at doses up to 1000 micro g/kg per day.

Cited by 10 publications

References 19 publications

Hematopoietic colony-stimulating factors: new players in tumor–nerve interactions

Hematopoietic colony-stimulating factors: new players in tumor–nerve interactions

Immunological and hematological effects of IL‐5(Rα)‐targeted therapy: An overview

GM‐CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid‐derived suppressor cells in vitro

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