Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma

Campo, Silvia; Serlupi-Crescenzi, Ottaviano; Arseni, Brunilde; Rossi, Stefania; Saggio, Isabella; Salone, B.; Cherubini, Gioia; Carminati, Paolo; Santis, Rita De

doi:10.1016/j.cyto.2005.06.006

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…25 Decreased circulating concentrations of sIL-6Ra have been reported in sepsis, along with an alteration of the IL-6-IL-6 receptor ''axis.'' 25,71,79 In contrast, serum sIL-6Ra concentrations have been reported to be elevated in several inflammatory diseases, but its levels did not change after stroke. 78,80 b Subunits.…”

Section: Interleukin-6-type Cytokine Receptorsmentioning

confidence: 95%

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

Jawa

Anillo

Huntoon

et al. 2011

J Intensive Care Med

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A variety of cytokines play a role in the response to an inflammatory stimulus. The interleukin-6 (IL-6)-type cytokines are released in response to tissue injury or an inflammatory stimulus. They act locally and systemically to generate a variety of physiologic responses, principal among them is the acute phase response. The IL-6 type cytokines demonstrate pleiotropy and redundancy of actions. This is made possible by the distinctive characteristics of the IL-6 receptor complex, which contains an ubiquitous subunit that is shared by most IL-6-type cytokines, as well as a cytokine-specific subunit.

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Section: Interleukin-6-type Cytokine Receptorsmentioning

confidence: 95%

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

Jawa

Anillo

Huntoon

et al. 2011

J Intensive Care Med

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“…The authors raised the possibility that other cytokines of the gp130 family participated in the in vivo growth of the lymphoma cells. 24 Murine IL-6 does not bind to the human IL-6R, but it can act on cells expressing human gp130 in conjunction with the soluble mouse IL-6R, i.e., by trans-signaling. 19 Therefore, the stimulation of INA-6.Tu1 cells by mouse IL-6/sIL-6R could potentially represent a paracrine growth mechanism in vivo.…”

Section: Discussionmentioning

confidence: 99%

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

et al. 2016

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IntroductionMultiple myeloma (MM) is characterized by the expansion of clonal plasma cells within the bone marrow (BM), leading to an M-protein in serum, antibody deficiency, and skeletal destruction. Despite stem cell transplantation and novel therapies, the vast majority of patients with MM will eventually relapse and become refractory to standard therapy. Treatment strategies specifically targeting mechanisms of tumor growth and survival are being intensely explored in MM in order to improve © Ferrata Storti Foundation patient outcome. 1In the pathogenesis of MM, genetic changes drive the development of the malignant clone, but the interaction between the malignant plasma cells and the BM microenvironment has been shown to be equally important in mediating myeloma cell survival and progression.2 One of the established pathogenic key factors produced in the BM milieu is interleukin(IL)-6, which promotes the growth and survival of the malignant plasma cells and mediates drug resistance.3 While some myeloma cells produce their own IL-6, 4 bone marrow stromal cells (BMSCs) are the main source, establishing a strong paracrine growth stimulation. 5 Other sources of IL-6 in MM are macrophages, osteoblasts and osteoclasts; 2 eosinophils and megakaryocytes may also contribute. 6The receptor for IL-6 comprises a specific α-receptor, glycoprotein (gp) 80 (CD126), which, after ligand binding, recruits the gp130 receptor (IL6ST, CD130). Gp130 is the common signal transducer for a family of cytokines with pleiotropic and partly redundant activities.7 While signaling via IL-6 and IL-11 is initiated via gp130 homodimerization, the receptor complexes of other family members consist of heterodimers of gp130 with a second signaling molecule, most of which use the leukemia inhibitory factor receptor (LIFR). Leukemia inhibitory factor (LIF) and oncostatin M (OSM) directly induce gp130/LIFR heterodimerization without the involvement of other receptor components. Upon dimerization, associated Janus kinases (JAKs) become activated and phosphorylate specific tyrosine residues on the receptors, which serve as docking sites for transcription factors and adaptor proteins. The main signaling pathways induced by gp130 are the activation of STAT (signal transducer and activator of transcription)-3, the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. 7,8The human plasma cell line INA-6 was generated in our laboratory from the pleural effusion of a patient with advanced plasma cell disease. 9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided. Despite the fact that murine IL-6 is not active on human cells, plasma cell tumors developed over a period of up to five months. In serum and ascites of tumor-beari...

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“…Recently, CytomX Therapeutics Inc. developed targeted "masked" antibodies, which are activated by disease-associated proteases (27). Sant7, a potent antagonist of the IL6 receptor, was engineered through targeted amino acid substitutions in key residues of the human IL6 molecule (28). Sant7 shows higher affinity than IL6 for the gp80 receptor subunit, but completely lacks binding capacity to the gp130 receptor signaling subunit.…”

Section: The Anti-il6 Drugsmentioning

confidence: 99%

Interleukin-6 as a Therapeutic Target

Rossi

Liu²,

Jourdan

et al. 2015

Clinical Cancer Research

314

277

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Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

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Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma

Cited by 10 publications

References 31 publications

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

Interleukin-6 as a Therapeutic Target

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